Alterations in Ca2+ Signalling via ER-Mitochondria Contact Site Remodelling in Cancer

  • Martijn Kerkhofs
  • Carlotta Giorgi
  • Saverio Marchi
  • Bruno Seitaj
  • Jan B. Parys
  • Paolo Pinton
  • Geert Bultynck
  • Mart Bittremieux
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 997)


Inter-organellar contact sites establish microdomains for localised Ca2+-signalling events. One of these microdomains is established between the ER and the mitochondria. Importantly, the so-called mitochondria-associated ER membranes (MAMs) contain, besides structural proteins and proteins involved in lipid exchange, several Ca2+-transport systems, mediating efficient Ca2+ transfer from the ER to the mitochondria. These Ca2+ signals critically control several mitochondrial functions, thereby impacting cell metabolism, cell death and survival, proliferation and migration. Hence, the MAMs have emerged as critical signalling hubs in physiology, while their dysregulation is an important factor that drives or at least contributes to oncogenesis and tumour progression. In this book chapter, we will provide an overview of the role of the MAMs in cell function and how alterations in the MAM composition contribute to oncogenic features and behaviours.


Calcium signaling Ca2+-transport systems IP3 receptors Voltage-dependent anion channels Chaperones Cell death and survival Mitochondrial bioenergetics Autophagy Mitochondria-associated ER membranes (MAMs) Cancer 



GB and JBP are supported by grants from the Research Foundation - Flanders (FWO) (grants G.0571.12N, G.0819.13N, G.0C91.14N, G.0927.15N and G.0A34.16N) and the Research Council - KU Leuven (OT14/101). MB and MK are holders of a Ph.D. Fellowship from the FWO. P.P. is grateful to Camilla degli Scrovegni for continuous support. P.P. is supported by Telethon (GGP15219/B), the Italian Association for Cancer Research (AIRC) (IG-14442), the Italian Cystic Fibrosis Research Foundation (19/2014), the Italian Ministry of Education, University and Research (COFIN no. 20129JLHSY_002, FIRB no. RBAP11FXBC_002 and Futuro in Ricerca no. RBFR10EGVP_001), local funds from the University of Ferrara and the Italian Ministry of Health. C.G is supported by AIRC (MFAG-13521), the Italian Ministry of Health, Cariplo and local funds from the University of Ferrara.


  1. Abu-Hamad S, Arbel N, Calo D, Arzoine L, Israelson A, Keinan N, Ben-Romano R, Friedman O, Shoshan-Barmatz V (2009) The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins. J Cell Sci 122:1906–1916PubMedCrossRefGoogle Scholar
  2. Ahmad A, Ahmad S, Schneider BK, Allen CB, Chang LY, White CW (2002) Elevated expression of hexokinase II protects human lung epithelial-like A549 cells against oxidative injury. Am J Physiol Lung Cell Mol Physiol 283:573–584CrossRefGoogle Scholar
  3. Akl H, Bultynck G (2013) Altered Ca2+ signaling in cancer cells: Proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochim Biophys Acta 1835:180–193PubMedGoogle Scholar
  4. Akl H, Monaco G, La Rovere R, Welkenhuyzen K, Kiviluoto S, Vervliet T, Molgó J, Distelhorst CW, Missiaen L, Mikoshiba K et al (2013) IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2. Cell Death Dis 4:e632PubMedPubMedCentralCrossRefGoogle Scholar
  5. Akl H, Vervloessem T, Kiviluoto S, Bittremieux M, Parys JB, De Smedt H, Bultynck G (2014) A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum. Biochim Biophys Acta 1843:2240–2252PubMedCrossRefGoogle Scholar
  6. Akl H, La Rovere RM, Janssens A, Vandenberghe P, Parys JB, Bultynck G (2015) HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor/Bcl-2 complexes. Int J Dev Biol 59:391–398PubMedCrossRefGoogle Scholar
  7. Arbel N, Ben-Hail D, Shoshan-Barmatz V (2012) Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem 287:23152–23161PubMedPubMedCentralCrossRefGoogle Scholar
  8. Arif T, Krelin Y, Shoshan-Barmatz V (2016) Reducing VDAC1 expression induces a non-apoptotic role for pro-apoptotic proteins in cancer cell differentiation. Biochim Biophys Acta 1857:1228–1242PubMedCrossRefGoogle Scholar
  9. Arzoine L, Zilberberg N, Ben-Romano R, Shoshan-Barmatz V (2009) Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity. J Biol Chem 284:3946–3955PubMedCrossRefGoogle Scholar
  10. Ashby MC, Tepikin AV (2001) ER calcium and the functions of intracellular organelles. Semin Cell Dev Biol 12:11–17PubMedCrossRefGoogle Scholar
  11. Aslan JE, You H, Williamson DM, Endig J, Youker RT, Thomas L, Shu H, Du Y, Milewski RL, Brush MH et al (2009) Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis. Mol Cell 34:497–509PubMedPubMedCentralCrossRefGoogle Scholar
  12. Assefa Z, Bultynck G, Szlufcik K, Nadif Kasri N, Vermassen E, Goris J, Missiaen L, Callewaert G, Parys JB, De Smedt H (2004) Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis. J Biol Chem 279:43227–43236PubMedCrossRefGoogle Scholar
  13. Atkins KM, Thomas LL, Barroso-González J, Thomas L, Auclair S, Yin J, Kang H, Chung JH, Dikeakos JD, Thomas G (2014) The multifunctional sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate p21-dependent cell-cycle arrest. Cell Rep 8:1545–1557PubMedPubMedCentralCrossRefGoogle Scholar
  14. Aydar E, Onganer P, Perrett R, Djamgoz MB, Palmer CP (2006) The expression and functional characterization of sigma (sigma) 1 receptors in breast cancer cell lines. Cancer Lett 242:245–257PubMedCrossRefGoogle Scholar
  15. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J 377:347–355PubMedPubMedCentralCrossRefGoogle Scholar
  16. Barroso-González J, Auclair S, Luan S, Thomas L, Atkins KM, Aslan JE, Thomas LL, Zhao J, Zhao Y, Thomas G (2016) PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage. Cell Death Differ 23:1448–1457PubMedCrossRefGoogle Scholar
  17. Báthori G, Csordás G, Garcia-Perez C, Davies E, Hajnóczky G (2006) Ca2+-dependent control of the permeability properties of the mitochondrial outer membrane and voltage-dependent anion-selective channel (VDAC). J Biol Chem 281:17347–17358PubMedCrossRefGoogle Scholar
  18. Ben-Porath I, Weinberg RA (2004) When cells get stressed: an integrative view of cellular senescence. J Clin Invest 113:8–13PubMedPubMedCentralCrossRefGoogle Scholar
  19. Bernardini JP, Lazarou M, Dewson G (2017) Parkin and mitophagy in cancer. Oncogene 36(10):1315–1327PubMedCrossRefGoogle Scholar
  20. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21PubMedCrossRefGoogle Scholar
  21. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529PubMedCrossRefGoogle Scholar
  22. Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN (2013) Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci USA 110:12526–12534PubMedPubMedCentralCrossRefGoogle Scholar
  23. Betzenhauser MJ, Wagner LE, Iwai M, Michikawa T, Mikoshiba K, Yule DI (2008) ATP modulation of Ca2+ release by type-2 and type-3 inositol (1, 4, 5)-triphosphate receptors. Differing ATP sensitivities and molecular determinants of action. J Biol Chem 283:21579–21587PubMedPubMedCentralCrossRefGoogle Scholar
  24. Bezprozvanny I, Watras J, Ehrlich BE (1991) Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351:751–754PubMedCrossRefGoogle Scholar
  25. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J et al (2005) ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 24:3470–3481PubMedPubMedCentralCrossRefGoogle Scholar
  26. Bittremieux M, Bultynck G (2015) p53 and Ca2+ signaling from the endoplasmic reticulum: partners in anti-cancer therapies. Oncoscience 2:233–238PubMedPubMedCentralCrossRefGoogle Scholar
  27. Bittremieux M, Parys JB, Pinton P, Bultynck G (2016) ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca2+ signaling. Biochim Biophys Acta 1863:1364–1378PubMedCrossRefGoogle Scholar
  28. Blackshaw S, Sawa A, Sharp AH, Ross CA, Snyder SH, Khan AA (2000) Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death. FASEB J Off Publ Fed Am Soc Exp Biol 14:1375–1379Google Scholar
  29. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D, Diehl JA (2010) PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29:3881–3895PubMedPubMedCentralCrossRefGoogle Scholar
  30. Bononi A, Bonora M, Marchi S, Missiroli S, Poletti F, Giorgi C, Pandolfi PP, Pinton P (2013) Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner. Cell Death Differ 20:1631–1643PubMedPubMedCentralCrossRefGoogle Scholar
  31. Bonora M, Giorgi C, Pinton P (2015) Novel frontiers in calcium signaling: A possible target for chemotherapy. Pharmacol Res 99:82–85PubMedCrossRefGoogle Scholar
  32. Bourougaa K, Naski N, Boularan C, Mlynarczyk C, Candeias M, Marullo S, Fåhraeus R (2010) Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol Cell 38:78–88PubMedCrossRefGoogle Scholar
  33. Boutin B, Tajeddine N, Monaco G, Molgo J, Vertommen D, Rider M, Parys JB, Bultynck G, Gailly P (2015) Endoplasmic reticulum Ca2+ content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation. Cell Calcium 57:312–320PubMedCrossRefGoogle Scholar
  34. Brahimi-Horn MC, Giuliano S, Saland E, Lacas-Gervais S, Sheiko T, Pelletier J, Bourget I, Bost F, Féral C, Boulter E et al (2015) Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation. Cancer Metab 3:8PubMedPubMedCentralCrossRefGoogle Scholar
  35. Breckenridge DG, Nguyen M, Kuppig S, Reth M, Shore GC (2002) The procaspase-8 isoform, procaspase-8L, recruited to the BAP31 complex at the endoplasmic reticulum. Proc Natl Acad Sci USA 99:4331–4336PubMedPubMedCentralCrossRefGoogle Scholar
  36. Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160:1115–1127PubMedPubMedCentralCrossRefGoogle Scholar
  37. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci USA 97:12625–12630PubMedPubMedCentralCrossRefGoogle Scholar
  38. Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB (2002) Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death. J Biol Chem 277:11392–11400PubMedCrossRefGoogle Scholar
  39. Bultynck G (2016) Onco-IP3Rs feed cancerous cravings for mitochondrial Ca2+. Trends Biochem Sci 41:390–393PubMedCrossRefGoogle Scholar
  40. Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 74:3735–3739PubMedPubMedCentralCrossRefGoogle Scholar
  41. Calì T, Ottolini D, Negro A, Brini M (2013) Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca2+transfer to sustain cell bioenergetics. Biochim Biophys Acta 1832:495–508PubMedCrossRefGoogle Scholar
  42. Campbell AM, Chan SHP (2007) The voltage dependent anion channel affects mitochondrial cholesterol distribution and function. Arch Biochem Biophys 466:203–210PubMedCrossRefGoogle Scholar
  43. Capiod T, Shuba Y, Skryma R, Prevarskaya N (2007) Calcium signalling and cancer cell growth. Subcell Biochem 45:405–427PubMedCrossRefGoogle Scholar
  44. Carafoli E (2012) The interplay of mitochondria with calcium: an historical appraisal. Cell Calcium 52:1–8PubMedCrossRefGoogle Scholar
  45. Cárdenas C, Foskett JK (2012) Mitochondrial Ca2+ signals in autophagy. Cell Calcium 52:44–51PubMedPubMedCentralCrossRefGoogle Scholar
  46. Cárdenas C, Miller RA, Smith I, Bui T, Molgó J, Müller M, Vais H, Cheung KH, Yang J, Parker I et al (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270–283PubMedPubMedCentralCrossRefGoogle Scholar
  47. Cárdenas C, Müller M, McNeal A, Lovy A, Jaňa F, Bustos G, Urra F, Smith N, Molgó J, Diehl JA, Ridky TW, Foskett JK (2016) Selective vulnerability of cancer cells by inhibition of Ca2+ transfer from endoplasmic reticulum to mitochondria. Cell Rep 14:2313–2324PubMedPubMedCentralCrossRefGoogle Scholar
  48. Chen AH, Silver PA (2012) Designing biological compartmentalization. Trends Cell Biol 22:662–670PubMedCrossRefGoogle Scholar
  49. Chen K-H, Guo X, Ma D, Guo Y, Li Q, Yang D, Li P, Qiu X, Wen S, Xiao R-P et al (2004) Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol 6:872–883PubMedCrossRefGoogle Scholar
  50. Chen Y-F, Chen Y-T, Chiu W-T, Shen M-R (2013) Remodeling of calcium signaling in tumor progression. J Biomed Sci 20:23PubMedPubMedCentralCrossRefGoogle Scholar
  51. Choe C-U, Ehrlich BE (2006) The inositol 1,4,5-trisphosphate receptor (IP3R) and its regulators: sometimes good and sometimes bad teamwork. Sci STKE 2006:re15Google Scholar
  52. Chu UB, Ruoho AE (2016) Biochemical pharmacology of the sigma-1 receptor. Mol Pharmacol 89:142–153PubMedCrossRefGoogle Scholar
  53. Clapham DE (2007) Calcium signaling. Cell 131:1047–1058PubMedCrossRefGoogle Scholar
  54. Collado M, Serrano M (2010) Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 10:51–57PubMedPubMedCentralCrossRefGoogle Scholar
  55. Colombini M (2012) VDAC structure, selectivity, and dynamics. Biochim Biophys Acta 1818:1457–1465PubMedPubMedCentralCrossRefGoogle Scholar
  56. Cosson P, Marchetti A, Ravazzola M, Orci L (2012) Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study. PloS One 7:e46293PubMedPubMedCentralCrossRefGoogle Scholar
  57. Crottès D, Martial S, Rapetti-Mauss R, Pisani DF, Loriol C, Pellissier B, Martin P, Chevet E, Borgese F, Soriani O (2011) Sig1R protein regulates hERG channel expression through a post-translational mechanism in leukemic cells. J Biol Chem 286:27947–27958PubMedPubMedCentralCrossRefGoogle Scholar
  58. Crottès D, Guizouarn H, Martin P, Borgese F, Soriani O (2013) The sigma-1 receptor: a regulator of cancer cell electrical plasticity? Membr Physiol Membr Biophys 4:175Google Scholar
  59. Csordás G, Thomas AP, Hajnóczky G (1999) Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J 18:96–108PubMedPubMedCentralCrossRefGoogle Scholar
  60. Csordás G, Renken C, Várnai P, Walter L, Weaver D, Buttle KF, Balla T, Mannella C, Hajnóczky G (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921PubMedPubMedCentralCrossRefGoogle Scholar
  61. Csordás G, Várnai P, Golenár T, Roy S, Purkins G, Schneider T, Balla T, Hajnóczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132PubMedPubMedCentralCrossRefGoogle Scholar
  62. Cullinan SB, Diehl JA (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279:20108–20117PubMedCrossRefGoogle Scholar
  63. Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63PubMedCrossRefGoogle Scholar
  64. da Silva WS, Gómez-Puyou A, de Gómez-Puyou MT, Moreno-Sanchez R, De Felice F, de Meis L, Oliveira MF, Galina A (2004) Mitochondrial bound hexokinase activity as a preventive antioxidant defense: steady-state ADP formation as a regulatory mechanism of membrane potential and reactive oxygen species generation in mitochondria. J Biol Chem 279:39846–39855CrossRefGoogle Scholar
  65. Davids MS, Letai A (2012) Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol 30:3127–3135PubMedPubMedCentralCrossRefGoogle Scholar
  66. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610PubMedCrossRefGoogle Scholar
  67. De Stefani D, Bononi A, Romagnoli A, Messina A, De Pinto V, Pinton P, Rizzuto R (2012) VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ 19:267–273PubMedCrossRefGoogle Scholar
  68. Decuypere J-P, Monaco G, Bultynck G, Missiaen L, De Smedt H, Parys JB (2011) The IP3 receptor-mitochondria connection in apoptosis and autophagy. Biochim Biophys Acta 1813:1003–1013PubMedCrossRefGoogle Scholar
  69. Delom F, Emadali A, Cocolakis E, Lebrun JJ, Nantel A, Chevet E (2007) Calnexin-dependent regulation of tunicamycin-induced apoptosis in breast carcinoma MCF-7 cells. Cell Death Differ 14:586–596PubMedCrossRefGoogle Scholar
  70. Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787:1309–1316PubMedCrossRefGoogle Scholar
  71. Diekmann Y, Pereira-Leal JB (2013) Evolution of intracellular compartmentalization. Biochem J 449:319–331PubMedCrossRefGoogle Scholar
  72. Ding Y, Gao H, Zhao L, Wang X, Zheng M (2015) Mitofusin 2-deficiency suppresses cell proliferation through disturbance of autophagy. PLoS One 10:e0121328PubMedPubMedCentralCrossRefGoogle Scholar
  73. Doghman-Bouguerra M, Granatiero V, Sbiera S, Sbiera I, Lacas-Gervais S, Brau S, Fassnacht M, Rizzuto R, Lalli E (2016) FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria. EMBO Rep 17:1264–1280PubMedCrossRefGoogle Scholar
  74. Dombernowsky SL, Samsøe-Petersen J, Petersen CH, Instrell R, Hedegaard AM, Thomas L, Atkins KM, Auclair S, Albrechtsen R, Mygind KJ et al (2015) The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. Nat Commun 6:7518PubMedPubMedCentralCrossRefGoogle Scholar
  75. Dong X-Y, Su Y-R, Qian X-P, Yang X-A, Pang X-W, Wu H-Y, Chen W-F (2003) Identification of two novel CT antigens and their capacity to elicit antibody response in hepatocellular carcinoma patients. Br J Cancer 89:291–297PubMedPubMedCentralCrossRefGoogle Scholar
  76. Eckenrode EF, Yang J, Velmurugan GV, Foskett JK, White C (2010) Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling. J Biol Chem 285:13678–13684PubMedPubMedCentralCrossRefGoogle Scholar
  77. Fan Z, Yu H, Cui N, Kong X, Liu X, Chang Y, Wu Y, Sun L, Wang G (2015) ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics. Exp Cell Res 335:68–81PubMedCrossRefGoogle Scholar
  78. Fedorenko OA, Popugaeva E, Enomoto M, Stathopulos PB, Ikura M, Bezprozvanny I (2014) Intracellular calcium channels: inositol-1,4,5-trisphosphate receptors. Eur J Pharmacol 739:39–48PubMedCrossRefGoogle Scholar
  79. Feng Y-X, Sokol ES, Del Vecchio CA, Sanduja S, Claessen JH, Proia TH, Jin DX, Reinhardt F, Ploegh HL, Wang Q, Gupta PB (2014) Epithelial-to-mesenchymal transition activates PERK-eIF2α and sensitizes cells to endoplasmic reticulum stress. Cancer Discov 4:702–715PubMedCrossRefGoogle Scholar
  80. Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci USA 112:2174–2181CrossRefGoogle Scholar
  81. Finch EA, Turner TJ, Goldin SM (1991) Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science 252:443–446PubMedCrossRefGoogle Scholar
  82. Flachbartová Z, Kovacech B (2013) Mortalin - a multipotent chaperone regulating cellular processes ranging from viral infection to neurodegeneration. Acta Virol 57:3–15PubMedCrossRefGoogle Scholar
  83. Foskett JK, White C, Cheung K-H, Mak D-OD (2007) Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 87:593–658PubMedPubMedCentralCrossRefGoogle Scholar
  84. Giampazolias E, Tait SWG (2016) Mitochondria and the hallmarks of cancer. FEBS J 283:803–814PubMedCrossRefGoogle Scholar
  85. Gincel D, Silberberg SD, Shoshan-Barmatz V (2000) Modulation of the voltage-dependent anion channel (VDAC) by glutamate. J Bioenerg Biomembr 32:571–583PubMedCrossRefGoogle Scholar
  86. Gincel D, Zaid H, Shoshan-Barmatz V (2001) Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. Biochem J 358:147–155PubMedPubMedCentralCrossRefGoogle Scholar
  87. Giorgi C, Ito K, Lin H-K, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R et al (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247–1251PubMedPubMedCentralCrossRefGoogle Scholar
  88. Giorgi C, Baldassari F, Bononi A, Bonora M, De Marchi E, Marchi S, Missiroli S, Patergnani S, Rimessi A, Suski JM et al (2012) Mitochondrial Ca2+ and apoptosis. Cell Calcium 52:36–43PubMedPubMedCentralCrossRefGoogle Scholar
  89. Giorgi C, Bonora M, Sorrentino G, Missiroli S, Poletti F, Suski JM, Galindo Ramirez F, Rizzuto R, Di Virgilio F, Zito E et al (2015a) p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner. Proc Natl Acad Sci USA 112:1779–1784PubMedPubMedCentralCrossRefGoogle Scholar
  90. Giorgi C, Missiroli S, Patergnani S, Duszynski J, Wieckowski MR, Pinton P (2015b) Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid Redox Signal 22:995–1019PubMedCrossRefGoogle Scholar
  91. Gniadecki R (2004) Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis. Biochem Biophys Res Commun 320:165–169PubMedCrossRefGoogle Scholar
  92. Gomez L, Thiebaut P-A, Paillard M, Ducreux S, Abrial M, Crola Da Silva C, Durand A, Alam MR, Van Coppenolle F, Sheu S-S et al (2016) The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury. Cell Death Differ 23:313–322PubMedCrossRefGoogle Scholar
  93. Greenberg EF, McColl KS, Zhong F, Wildey G, Dowlati A, Distelhorst CW (2015) Synergistic killing of human small cell lung cancer cells by the Bcl-2-inositol 1,4,5-trisphosphate receptor disruptor BIRD-2 and the BH3-mimetic ABT-263. Cell Death Dis 6:e2034PubMedPubMedCentralCrossRefGoogle Scholar
  94. Guicciardi ME, Werneburg NW, Bronk SF, Franke A, Yagita H, Thomas G, Gores GJ (2014) Cellular inhibitor of apoptosis (cIAP)-mediated ubiquitination of phosphofurin acidic cluster sorting protein 2 (PACS-2) negatively regulates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity. PloS One 9:e92124PubMedPubMedCentralCrossRefGoogle Scholar
  95. Guo X, Chen K-H, Guo Y, Liao H, Tang J, Xiao R-P (2007) Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway. Circ Res 101:1113–1122PubMedCrossRefGoogle Scholar
  96. Guo W, Yan L, Yang L, Liu X, E Q, Gao P, Ye X, Liu W, Zuo J (2014) Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma. PloS One 9:e85766Google Scholar
  97. Gutstein DE, Marks AR (1997) Role of inositol 1,4,5-trisphosphate receptors in regulating apoptotic signaling and heart failure. Heart Vessels Suppl 12:53–57CrossRefGoogle Scholar
  98. Hajnóczky G, Robb-Gaspers LD, Seitz MB, Thomas AP (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82:415–424PubMedCrossRefGoogle Scholar
  99. Hajnóczky G, Csordás G, Yi M (2002) Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria. Cell Calcium 32:363–377PubMedCrossRefGoogle Scholar
  100. Halestrap AP (2014) The C ring of the F1Fo ATP synthase forms the mitochondrial permeability transition pore: a critical appraisal. Front Oncol 4:234PubMedPubMedCentralCrossRefGoogle Scholar
  101. Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA (2005) PERK and GCN2 contribute to eIF2α phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 16:5493–5501PubMedPubMedCentralCrossRefGoogle Scholar
  102. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  103. Hanson CJ, Bootman MD, Distelhorst CW, Wojcikiewicz RJ, Roderick HL (2008) Bcl-2 suppresses Ca2+ release through inositol 1,4,5-trisphosphate receptors and inhibits Ca2+ uptake by mitochondria without affecting ER calcium store content. Cell Calcium 44:324–338PubMedCrossRefGoogle Scholar
  104. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904PubMedCrossRefGoogle Scholar
  105. Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M (2012) ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest 122:4621–4634PubMedPubMedCentralCrossRefGoogle Scholar
  106. Hauet T, Yao Z-X, Bose HS, Wall CT, Han Z, Li W, Hales DB, Miller WL, Culty M, Papadopoulos V (2005) Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into leydig cell mitochondria. Mol Endocrinol Baltim Md 19:540–554CrossRefGoogle Scholar
  107. Hayashi T, Su T-P (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596–610PubMedCrossRefGoogle Scholar
  108. Hebert DN, Foellmer B, Helenius A (1995) Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 81:425–433PubMedCrossRefGoogle Scholar
  109. Hodge T, Colombini M (1997) Regulation of metabolite flux through voltage-gating of VDAC channels. J Membr Biol 157:271–279PubMedCrossRefGoogle Scholar
  110. Huang H, Shah K, Bradbury NA, Li C, White C (2014) Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation. Cell Death Dis 5:e1482PubMedPubMedCentralCrossRefGoogle Scholar
  111. Huang X, Jin M, Chen Y-X, Wang J, Zhai K, Chang Y, Yuan Q, Yao K-T, Ji G (2016) ERP44 inhibits human lung cancer cell migration mainly via IP3R2. Aging 8:1276–1286PubMedPubMedCentralCrossRefGoogle Scholar
  112. Iino M (1990) Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca release in smooth muscle cells of the guinea pig taenia caeci. J Gen Physiol 95:1103–1122PubMedCrossRefGoogle Scholar
  113. Jayaraman T, Marks AR (1997) T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis. Mol Cell Biol 17:3005–3012PubMedPubMedCentralCrossRefGoogle Scholar
  114. Jin H, Ji M, Chen L, Liu Q, Che S, Xu M, Lin Z (2016) The clinicopathological significance of Mortalin overexpression in invasive ductal carcinoma of breast. J Exp Clin Cancer Res CR 35:42PubMedCrossRefGoogle Scholar
  115. Jonas EA, Porter GA, Beutner G, Mnatsakanyan N, Alavian KN (2015) Cell death disguised: the mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase. Pharmacol Res 99:382–392PubMedPubMedCentralCrossRefGoogle Scholar
  116. Joseph SK, Hajnóczky G (2007) IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond. Apoptosis Int J Program Cell Death 12:951–968CrossRefGoogle Scholar
  117. Kang SS, Han K-S, Ku BM, Lee YK, Hong J, Shin HY, Almonte AG, Woo DH, Brat DJ, Hwang EM et al (2010) Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival. Cancer Res 70:1173–1183PubMedPubMedCentralCrossRefGoogle Scholar
  118. Kang T-W, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A et al (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–551PubMedCrossRefGoogle Scholar
  119. Kannan A, Wells RB, Sivakumar S, Komatsu S, Singh KP, Samten B, Philley JV, Sauter ER, Ikebe M, Idell S et al (2016) Mitochondrial reprogramming regulates breast cancer progression. Clin Cancer Res 22:3348–3360PubMedCrossRefGoogle Scholar
  120. Kaufman RJ, Malhotra JD (2014) Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics. Biochim Biophys Acta 1843:2233–2239PubMedPubMedCentralCrossRefGoogle Scholar
  121. Kaul SC, Duncan EL, Englezou A, Takano S, Reddel RR, Mitsui Y, Wadhwa R (1998) Malignant transformation of NIH3T3 cells by overexpression of mot-2 protein. Oncogene 17:907–911PubMedCrossRefGoogle Scholar
  122. Kaul SC, Reddel RR, Mitsui Y, Wadhwa R (2001) An N-terminal region of mot-2 binds to p53 in vitro. Neoplasia N Y N 3:110–114CrossRefGoogle Scholar
  123. Kaul SC, Aida S, Yaguchi T, Kaur K, Wadhwa R (2005) Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J Biol Chem 280:39373–39379PubMedCrossRefGoogle Scholar
  124. Khan MT, Wagner L, Yule DI, Bhanumathy C, Joseph SK (2006) Akt kinase phosphorylation of inositol 1,4,5-trisphosphate receptors. J Biol Chem 281:3731–3737PubMedCrossRefGoogle Scholar
  125. Kliková K, Štefaniková A, Pilchová I, Hatok J, Chudý P, Chudej J, Dobrota D, Račay P (2015) Differential impact of bortezomib on HL-60 and K562 cells. Gen Physiol Biophys 34:33–42PubMedCrossRefGoogle Scholar
  126. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T (2007) ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14:230–239PubMedCrossRefGoogle Scholar
  127. Krols M, Bultynck G, Janssens S (2016) ER-Mitochondria contact sites: a new regulator of cellular calcium flux comes into play. J Cell Biol 214:367–370PubMedPubMedCentralCrossRefGoogle Scholar
  128. Kronidou NG, Oppliger W, Bolliger L, Hannavy K, Glick BS, Schatz G, Horst M (1994) Dynamic interaction between Isp45 and mitochondrial hsp70 in the protein import system of the yeast mitochondrial inner membrane. Proc Natl Acad Sci USA 91:12818–12822PubMedPubMedCentralCrossRefGoogle Scholar
  129. La Rovere RM, Roest G, Bultynck G, Parys JB (2016) Intracellular Ca2+ signaling and Ca2+microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium 60:74–87PubMedCrossRefGoogle Scholar
  130. Lakkaraju AKK, van der Goot FG (2013) Calnexin controls the STAT3-mediated transcriptional response to EGF. Mol Cell 51:386–396PubMedCrossRefGoogle Scholar
  131. Lamriben L, Graham JB, Adams BM, Hebert DN (2016) N-Glycan-based ER molecular chaperone and protein quality control system: the Calnexin binding cycle. Traffic Cph Den 17:308–326CrossRefGoogle Scholar
  132. Lavik AR, Zhong F, Chang M-J, Greenberg E, Choudhary Y, Smith MR, McColl KS, Pink J, Reu FJ, Matsuyama S et al (2015) A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2. Oncotarget 6:27388–27402PubMedPubMedCentralCrossRefGoogle Scholar
  133. Li J, Lee B, Lee AS (2006) Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 281:7260–7270PubMedCrossRefGoogle Scholar
  134. Li C, Wang X, Vais H, Thompson CB, Foskett JK, White C (2007) Apoptosis regulation by Bcl-xL modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gating. Proc Natl Acad Sci USA 104:12565–12570PubMedPubMedCentralCrossRefGoogle Scholar
  135. Li G, Mongillo M, Chin K-T, Harding H, Ron D, Marks AR, Tabas I (2009) Role of ERO1-α-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 186:783–792PubMedPubMedCentralCrossRefGoogle Scholar
  136. Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–218PubMedPubMedCentralCrossRefGoogle Scholar
  137. Liou G-Y, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44:479–496PubMedCrossRefGoogle Scholar
  138. Liu J, Rone MB, Papadopoulos V (2006) Protein-protein interactions mediate mitochondrial cholesterol transport and steroid biosynthesis. J Biol Chem 281:38879–38893PubMedCrossRefGoogle Scholar
  139. Lou Y, Li R, Liu J, Zhang Y, Zhang X, Jin B, Liu Y, Wang Z, Zhong H, Wen S et al (2015) Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma. Med Oncol 32:132PubMedCrossRefGoogle Scholar
  140. Lou Y, Zhang Y, Li R, Gu P, Xiong L, Zhong H, Zhang W, Han B (2016) Transcriptional profiling revealed the anti-proliferative effect of MFN2 deficiency and identified risk factors in lung adenocarcinoma. Tumor Biol 37:8643–8655CrossRefGoogle Scholar
  141. Lu J, Tan M, Cai Q (2015) The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett 356:156–164PubMedCrossRefGoogle Scholar
  142. Lynes EM, Bui M, Yap MC, Benson MD, Schneider B, Ellgaard L, Berthiaume LG, Simmen T (2012) Palmitoylated TMX and calnexin target to the mitochondria-associated membrane. EMBO J 31:457–470PubMedCrossRefGoogle Scholar
  143. Lynes EM, Raturi A, Shenkman M, Ortiz Sandoval C, Yap MC, Wu J, Janowicz A, Myhill N, Benson MD, Campbell RE et al (2013) Palmitoylation is the switch that assigns calnexin to quality control or ER Ca2+ signaling. J Cell Sci 126:3893–3903PubMedCrossRefGoogle Scholar
  144. Ma LI, Chang Y, Yu L, He W, Liu Y (2015) Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells. Oncol Lett 10:3816–3822PubMedPubMedCentralGoogle Scholar
  145. Maldonado EN, Patnaik J, Mullins MR, Lemasters JJ (2010) Free tubulin modulates mitochondrial membrane potential in cancer cells. Cancer Res 70:10192–10201PubMedPubMedCentralCrossRefGoogle Scholar
  146. Marchi S, Pinton P (2014) The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications. J Physiol 592:829–839PubMedPubMedCentralCrossRefGoogle Scholar
  147. Marchi S, Pinton P (2016) Alterations of calcium homeostasis in cancer cells. Curr Opin Pharmacol 29:1–6PubMedCrossRefGoogle Scholar
  148. Marchi S, Rimessi A, Giorgi C, Baldini C, Ferroni L, Rizzuto R, Pinton P (2008) Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuli. Biochem Biophys Res Commun 375:501–505PubMedPubMedCentralCrossRefGoogle Scholar
  149. Marchi S, Marinello M, Bononi A, Bonora M, Giorgi C, Rimessi A, Pinton P (2012) Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis. Cell Death Dis 3:e304PubMedPubMedCentralCrossRefGoogle Scholar
  150. Marchi S, Giorgi C, Oparka M, Duszynski J, Wieckowski MR, Pinton P (2014a) Oncogenic and oncosuppressive signal transduction at mitochondria-associated endoplasmic reticulum membranes. Mol Cell Oncol 1:956469CrossRefGoogle Scholar
  151. Marchi S, Patergnani S, Pinton P (2014b) The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta 1837:461–469PubMedCrossRefGoogle Scholar
  152. Mavlyutov TA, Epstein M, Guo L-W (2015) Subcellular localization of the sigma-1 receptor in retinal neurons - an electron microscopy study. Sci Rep 5:10689PubMedPubMedCentralCrossRefGoogle Scholar
  153. Maxfield KE, Taus PJ, Corcoran K, Wooten J, Macion J, Zhou Y, Borromeo M, Kollipara RK, Yan J, Xie J et al (2015) Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer. Nat Commun 6:8840PubMedPubMedCentralCrossRefGoogle Scholar
  154. McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci USA 89:3170–3174PubMedPubMedCentralCrossRefGoogle Scholar
  155. Mendes CCP, Gomes DA, Thompson M, Souto NC, Goes TS, Goes AM, Rodrigues MA, Gomez MV, Nathanson MH, Leite MF (2005) The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J Biol Chem 280:40892–40900PubMedCrossRefGoogle Scholar
  156. Messina A, Reina S, Guarino F, De Pinto V (2012) VDAC isoforms in mammals. Biochim Biophys Acta 1818:1466–1476PubMedCrossRefGoogle Scholar
  157. Mikoshiba K (2007) The IP3 receptor/Ca2+ channel and its cellular function. Biochem Soc Symp:9–22Google Scholar
  158. Missiroli S, Bonora M, Patergnani S, Poletti F, Perrone M, Gafà R, Magri E, Raimondi A, Lanza G, Tacchetti C, Kroemer G, Pandolfi PP, Pinton P, Giorgi C (2016) PML at mitochondria-associated membranes is critical for the repression of autophagy and cancer development. Cell Rep 16:2415–2427PubMedPubMedCentralCrossRefGoogle Scholar
  159. Miyakawa T, Maeda A, Yamazawa T, Hirose K, Kurosaki T (1999) Encoding of Ca2+ signals by differential expression of IP3 receptor subtypes. EMBO J 18:1303–1308PubMedPubMedCentralCrossRefGoogle Scholar
  160. Monaco G, Decrock E, Akl H, Ponsaerts R, Vervliet T, Luyten T, De Maeyer M, Missiaen L, Distelhorst CW, De Smedt H et al (2012) Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl. Cell Death Differ 19:295–309PubMedCrossRefGoogle Scholar
  161. Monaco G, Decrock E, Arbel N, van Vliet AR, La Rovere RM, De Smedt H, Parys JB, Agostinis P, Leybaert L, Shoshan-Barmatz V et al (2015) The BH4 domain of anti-apoptotic Bcl-XL, but not that of the related Bcl-2, limits the voltage-dependent anion channel 1 (VDAC1)-mediated transfer of pro-apoptotic Ca2+ signals to mitochondria. J Biol Chem 290:9150–9161PubMedPubMedCentralCrossRefGoogle Scholar
  162. Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R, Wieckowski MR, Campo G, Pinton P (2015) Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. J Mol Cell Cardiol 78:142–153PubMedCrossRefGoogle Scholar
  163. Mori T, Hayashi T, Hayashi E, Su T-P (2013) Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PloS One 8:e76941PubMedPubMedCentralCrossRefGoogle Scholar
  164. Mound A, Rodat-Despoix L, Bougarn S, Ouadid-Ahidouch H, Matifat F (2013) Molecular interaction and functional coupling between type 3 inositol 1,4,5-trisphosphate receptor and BKCa channel stimulate breast cancer cell proliferation. Eur J Cancer Oxf Engl 1990 49:3738–3751Google Scholar
  165. Mujcic H, Nagelkerke A, Rouschop KMA, Chung S, Chaudary N, Span PN, Clarke B, Milosevic M, Sykes J, Hill RP et al (2013) Hypoxic activation of the PERK/eIF2α arm of the unfolded protein response promotes metastasis through induction of LAMP3. Clin Cancer Res 19:6126–6137PubMedCrossRefGoogle Scholar
  166. Myhill N, Lynes EM, Nanji JA, Blagoveshchenskaya AD, Fei H, Carmine Simmen K, Cooper TJ, Thomas G, Simmen T (2008) The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell 19:2777–2788PubMedPubMedCentralCrossRefGoogle Scholar
  167. Nagelkerke A, Bussink J, Mujcic H, Wouters BG, Lehmann S, Sweep FC, Span PN (2013) Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res BCR 15:R2PubMedCrossRefGoogle Scholar
  168. Nagelkerke A, Sweep FC, Stegeman H, Grénman R, Kaanders JH, Bussink J, Span PN (2015) Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma. Head Neck 37:896–905PubMedCrossRefGoogle Scholar
  169. Naon D, Scorrano L (2014) At the right distance: ER-mitochondria juxtaposition in cell life and death. Biochim Biophys Acta 1843:2184–2194PubMedCrossRefGoogle Scholar
  170. Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, Serafini A, Semenzato M, Herkenne S, Hernández-Alvarez MI et al (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci USA 113:11249–11254PubMedPubMedCentralCrossRefGoogle Scholar
  171. Newton CL, Mignery GA, Südhof TC (1994) Co-expression in vertebrate tissues and cell lines of multiple inositol 1,4,5-trisphosphate (InsP3) receptors with distinct affinities for InsP3. J Biol Chem 269:28613–28619PubMedGoogle Scholar
  172. Ono Y, Tamiya T, Ichikawa T, Matsumoto K, Furuta T, Ohmoto T, Akiyama K, Seki S, Ueki K, Louis DN (1997) Accumulation of wild-type p53 in astrocytomas is associated with increased p21 expression. Acta Neuropathol (Berl) 94:21–27CrossRefGoogle Scholar
  173. Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552–565PubMedCrossRefGoogle Scholar
  174. Ouyang K, Leandro Gomez-Amaro R, Stachura DL, Tang H, Peng X, Fang X, Traver D, Evans SM, Chen J (2014) Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia. Nat Commun 5:4814PubMedPubMedCentralCrossRefGoogle Scholar
  175. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389PubMedCrossRefGoogle Scholar
  176. Palmer CP, Mahen R, Schnell E, Djamgoz MB, Aydar E (2007) Sigma-1 receptors bind cholesterol and remodel lipid rafts in breast cancer cell lines. Cancer Res 67:11166–11175PubMedCrossRefGoogle Scholar
  177. Panieri E, Santoro MM (2016) ROS homeostasis and metabolism: a dangerous liaison in cancer cells. Cell Death Dis 7:e2253PubMedPubMedCentralCrossRefGoogle Scholar
  178. Parys JB, De Smedt H (2012) Inositol 1,4,5-trisphosphate and its receptors. Adv Exp Med Biol 740:255–279PubMedCrossRefGoogle Scholar
  179. Parys JB, Sernett SW, DeLisle S, Snyder PM, Welsh MJ, Campbell KP (1992) Isolation, characterization, and localization of the inositol 1,4,5-trisphosphate receptor protein in Xenopus laevis oocytes. J Biol Chem 267:18776–18782PubMedGoogle Scholar
  180. Pastorino JG, Hoek JB (2008) Regulation of hexokinase binding to VDAC. J Bioenerg Biomembr 40:171–182PubMedPubMedCentralCrossRefGoogle Scholar
  181. Pedersen PL (2008) Voltage dependent anion channels (VDACs): a brief introduction with a focus on the outer mitochondrial compartment’s roles together with hexokinase-2 in the “Warburg effect” in cancer. J Bioenerg Biomembr 40:123–126PubMedCrossRefGoogle Scholar
  182. Pierro C, Cook SJ, Foets TC, Bootman MD, Roderick HL (2014) Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodelling of the isoform composition of IP3Rs and ER luminal Ca2+ levels in colorectal cancer cell lines. J Cell Sci 127:1607–1619PubMedCrossRefGoogle Scholar
  183. Pillozzi S, Brizzi MF, Bernabei PA, Bartolozzi B, Caporale R, Basile V, Boddi V, Pegoraro L, Becchetti A, Arcangeli A (2007) VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome. Blood 110:1238–1250PubMedCrossRefGoogle Scholar
  184. Pillozzi S, Masselli M, De Lorenzo E, Accordi B, Cilia E, Crociani O, Amedei A, Veltroni M, D’Amico M, Basso G, Becchetti A, Campana D, Arcangeli A (2011) Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers. Blood 117:902–914PubMedCrossRefGoogle Scholar
  185. Pinton P, Giorgi C, Pandolfi PP (2011) The role of PML in the control of apoptotic cell fate: a new key player at ER–mitochondria sites. Cell Death Differ 18:1450–1456PubMedPubMedCentralCrossRefGoogle Scholar
  186. Pluquet O, Qu L-K, Baltzis D, Koromilas AE (2005) Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3β. Mol Cell Biol 25:9392–9405PubMedPubMedCentralCrossRefGoogle Scholar
  187. Prevarskaya N, Ouadid-Ahidouch H, Skryma R, Shuba Y (2014) Remodelling of Ca2+ transport in cancer: how it contributes to cancer hallmarks? Philos Trans R Soc Lond B Biol Sci 369:20130097PubMedPubMedCentralCrossRefGoogle Scholar
  188. Qiao A, Wang K, Yuan Y, Guan Y, Ren X, Li L, Chen X, Li F, Chen AF, Zhou J et al (2016) Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia. Oncotarget 7:43390–43400PubMedPubMedCentralCrossRefGoogle Scholar
  189. Qu L, Huang S, Baltzis D, Rivas-Estilla AM, Pluquet O, Hatzoglou M, Koumenis C, Taya Y, Yoshimura A, Koromilas AE (2004) Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β. Genes Dev 18:261–277PubMedPubMedCentralCrossRefGoogle Scholar
  190. Raffaello A, Mammucari C, Gherardi G, Rizzuto R (2016) Calcium at the center of Cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 41(12):1035–1049PubMedCrossRefGoogle Scholar
  191. Ran Q, Wadhwa R, Kawai R, Kaul SC, Sifers RN, Bick RJ, Smith JR, Pereira-Smith OM (2000) Extramitochondrial localization of mortalin/mthsp70/PBP74/GRP75. Biochem Biophys Res Commun 275:174–179PubMedCrossRefGoogle Scholar
  192. Ranieri M, Brajkovic S, Riboldi G, Ronchi D, Rizzo F, Bresolin N, Corti S, Comi GP (2013) Mitochondrial fusion proteins and human diseases. Neurol Res Int 2013:293893PubMedPubMedCentralCrossRefGoogle Scholar
  193. Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE, Rizzuto R (2002) Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol 159:613–624PubMedPubMedCentralCrossRefGoogle Scholar
  194. Raturi A, Gutiérrez T, Ortiz-Sandoval C, Ruangkittisakul A, Herrera-Cruz MS, Rockley JP, Gesson K, Ourdev D, Lou P-H, Lucchinetti E (2016) TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux. J Cell Biol 214:433–444PubMedPubMedCentralCrossRefGoogle Scholar
  195. Rieusset J, Fauconnier J, Paillard M, Belaidi E, Tubbs E, Chauvin MA, Durand A, Bravard A, Teixeira G, Bartosch B (2016) Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance. Diabetologia 59:614–623PubMedCrossRefGoogle Scholar
  196. Rizzuto R, Brini M, Murgia M, Pozzan T (1993) Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262:744–747PubMedCrossRefGoogle Scholar
  197. Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, Tuft RA, Pozzan T (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280:1763–1766PubMedCrossRefGoogle Scholar
  198. Rizzuto R, Bernardi P, Pozzan T (2000) Mitochondria as all-round players of the calcium game. J Physiol 529(Pt 1):37–47PubMedPubMedCentralCrossRefGoogle Scholar
  199. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Bio 13:566–578CrossRefGoogle Scholar
  200. Roderick HL, Cook SJ (2008) Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer 8:361–375PubMedCrossRefGoogle Scholar
  201. Roderick HL, Lechleiter JD, Camacho P (2000) Cytosolic phosphorylation of calnexin controls intracellular Ca2+oscillations via an interaction with SERCA2b. J Cell Biol 149:1235–1248PubMedPubMedCentralCrossRefGoogle Scholar
  202. Rone MB, Midzak AS, Issop L, Rammouz G, Jagannathan S, Fan J, Ye X, Blonder J, Veenstra T, Papadopoulos V (2012) Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones. Mol Endocrinol Baltim Md 26:1868–1882CrossRefGoogle Scholar
  203. Rong Y-P, Aromolaran AS, Bultynck G, Zhong F, Li X, McColl K, Matsuyama S, Herlitze S, Roderick HL, Bootman MD et al (2008) Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2’s inhibition of apoptotic calcium signals. Mol Cell 31:255–265PubMedPubMedCentralCrossRefGoogle Scholar
  204. Rong Y-P, Bultynck G, Aromolaran AS, Zhong F, Parys JB, De Smedt H, Mignery GA, Roderick HL, Bootman MD, Distelhorst CW (2009) The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci USA 106:14397–14402PubMedPubMedCentralCrossRefGoogle Scholar
  205. Rostovtseva TK, Bezrukov SM (2012) VDAC inhibition by tubulin and its physiological implications. Biochim Biophys Acta 1818:1526–1535PubMedCrossRefGoogle Scholar
  206. Rostovtseva TK, Kazemi N, Weinrich M, Bezrukov SM (2006) Voltage gating of VDAC is regulated by nonlamellar lipids of mitochondrial membranes. J Biol Chem 281:37496–37506PubMedCrossRefGoogle Scholar
  207. Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V, Bezrukov SM, Sackett DL (2008) Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci USA 105:18746–18751PubMedPubMedCentralCrossRefGoogle Scholar
  208. Rouschop KMA, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW et al (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120:127–141PubMedCrossRefGoogle Scholar
  209. Rowland AA, Voeltz GK (2012) Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol 13:607–625PubMedPubMedCentralCrossRefGoogle Scholar
  210. Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta 1833:3460–3470PubMedCrossRefGoogle Scholar
  211. Schein SJ, Colombini M, Finkelstein A (1976) Reconstitution in planar lipid bilayers of a voltage-dependent anion-selective channel obtained from paramecium mitochondria. J Membr Biol 30:99–120PubMedCrossRefGoogle Scholar
  212. Scherer PE, Manning-Krieg UC, Jenö P, Schatz G, Horst M (1992) Identification of a 45-kDa protein at the protein import site of the yeast mitochondrial inner membrane. Proc Natl Acad Sci USA 89:11930–11934PubMedPubMedCentralCrossRefGoogle Scholar
  213. Schneider HC, Westermann B, Neupert W, Brunner M (1996) The nucleotide exchange factor MGE exerts a key function in the ATP-dependent cycle of mt-Hsp70-Tim44 interaction driving mitochondrial protein import. EMBO J 15:5796–5803PubMedPubMedCentralGoogle Scholar
  214. Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487PubMedCrossRefGoogle Scholar
  215. Shimizu S, Konishi A, Kodama T, Tsujimoto Y (2000) BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc Natl Acad Sci USA 97:3100–3105PubMedPubMedCentralCrossRefGoogle Scholar
  216. Shioda N, Ishikawa K, Tagashira H, Ishizuka T, Yawo H, Fukunaga K (2012) Expression of a truncated form of the endoplasmic reticulum chaperone protein, σ1 receptor, promotes mitochondrial energy depletion and apoptosis. J Biol Chem 287:23318–23331PubMedPubMedCentralCrossRefGoogle Scholar
  217. Shoshan-Barmatz V, Gincel D (2003) The voltage-dependent anion channel: characterization, modulation, and role in mitochondrial function in cell life and death. Cell Biochem Biophys 39:279–292PubMedCrossRefGoogle Scholar
  218. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 31:227–285PubMedCrossRefGoogle Scholar
  219. Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y, Feliciangeli SF, Hung C-H, Crump CM, Thomas G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24:717–729PubMedPubMedCentralCrossRefGoogle Scholar
  220. Simpson AJ, Caballero OL, Jungbluth A, Chen Y-T, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5:615–625PubMedCrossRefGoogle Scholar
  221. Skrzycki M, Czeczot H (2013) Altered expression level of Sigma1 receptor gene in human colorectal cancer. J Recept Signal Transduct Res 33:313–318PubMedCrossRefGoogle Scholar
  222. Starenki D, Hong S-K, Lloyd RV, Park J-I (2015) Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene 34:4624–4634PubMedCrossRefGoogle Scholar
  223. Stewart TA, Yapa KTDS, Monteith GR (2015) Altered calcium signaling in cancer cells. Biochim Biophys Acta 1848:2502–2511PubMedCrossRefGoogle Scholar
  224. Su TP (1982) Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther 223:284–290PubMedGoogle Scholar
  225. Su T-P, Hayashi T, Maurice T, Buch S, Ruoho AE (2010) The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31:557–566PubMedPubMedCentralCrossRefGoogle Scholar
  226. Sun L, Shukair S, Naik TJ, Moazed F, Ardehali H (2008) Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II. Mol Cell Biol 28:1007–1017PubMedCrossRefGoogle Scholar
  227. Szabadkai G, Bianchi K, Várnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911PubMedPubMedCentralCrossRefGoogle Scholar
  228. Szado T, Vanderheyden V, Parys JB, De Smedt H, Rietdorf K, Kotelevets L, Chastre E, Khan F, Landegren U, Söderberg O et al (2008) Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc Natl Acad Sci USA 105:2427–2432PubMedPubMedCentralCrossRefGoogle Scholar
  229. Szatkowski C, Parys JB, Ouadid-Ahidouch H, Matifat F (2010) Inositol 1,4,5-trisphosphate-induced Ca2+ signalling is involved in estradiol-induced breast cancer epithelial cell growth. Mol Cancer 9:156PubMedPubMedCentralCrossRefGoogle Scholar
  230. Tagashira H, Bhuiyan MS, Shioda N, Fukunaga K (2014) Fluvoxamine rescues mitochondrial Ca2+ transport and ATP production through σ(1)-receptor in hypertrophic cardiomyocytes. Life Sci 95:89–100PubMedCrossRefGoogle Scholar
  231. Takizawa T, Tatematsu C, Watanabe K, Kato K, Nakanishi Y (2004) Cleavage of calnexin caused by apoptotic stimuli: implication for the regulation of apoptosis. J Biochem (Tokyo) 136:399–405CrossRefGoogle Scholar
  232. Tsai S-YA, Chuang J-Y, Tsai M-S, Wang X-F, Xi Z-X, Hung J-J, Chang W-C, Bonci A, Su T-P (2015) Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Proc Natl Acad Sci USA 112:6562–6570CrossRefGoogle Scholar
  233. Tsunoda T, Koga H, Yokomizo A, Tatsugami K, Eto M, Inokuchi J, Hirata A, Masuda K, Okumura K, Naito S (2005) Inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP3R1) modulates the acquisition of cisplatin resistance in bladder cancer cell lines. Oncogene 24:1396–1402PubMedCrossRefGoogle Scholar
  234. Tu H, Wang Z, Bezprozvanny I (2005) Modulation of mammalian inositol 1,4,5-trisphosphate receptor isoforms by calcium: a role of calcium sensor region. Biophys J 88:1056–1069PubMedCrossRefGoogle Scholar
  235. Urra H, Dufey E, Avril T, Chevet E, Hetz C (2016) Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer 2:252–262PubMedCrossRefGoogle Scholar
  236. van Riggelen J, Yetil A, Felsher DW (2010) MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer 10:301–309PubMedCrossRefGoogle Scholar
  237. van Vliet AR, Verfaillie T, Agostinis P (2014) New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta 1843:2253–2262PubMedCrossRefGoogle Scholar
  238. Vance JE (2014) MAM (mitochondria-associated membranes) in mammalian cells: Lipids and beyond. Biochim Biophys Acta 1841:595–609PubMedCrossRefGoogle Scholar
  239. Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB (2000) Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc Natl Acad Sci USA 97:4666–4671PubMedPubMedCentralCrossRefGoogle Scholar
  240. Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M (2001) Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem 276:19414–19419PubMedCrossRefGoogle Scholar
  241. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033PubMedPubMedCentralCrossRefGoogle Scholar
  242. Vanderheyden V, Devogelaere B, Missiaen L, De Smedt H, Bultynck G, Parys JB (2009) Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation. Biochim Biophys Acta 1793:959–970PubMedCrossRefGoogle Scholar
  243. Várnai P, Balla A, Hunyady L, Balla T (2005) Targeted expression of the inositol 1,4,5-triphosphate receptor (IP3R) ligand-binding domain releases Ca2+ via endogenous IP3R channels. Proc Natl Acad Sci USA 102:7859–7864PubMedPubMedCentralCrossRefGoogle Scholar
  244. Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, Piette J, Linehan C, Gupta S, Samali A, Agostinis P (2012) PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ 19:1880–1891PubMedPubMedCentralCrossRefGoogle Scholar
  245. Vervliet T, Parys JB, Bultynck G (2016) Bcl-2 proteins and calcium signaling: complexity beneath the surface. Oncogene 35:5079–5092PubMedCrossRefGoogle Scholar
  246. Vervloessem T, Yule DI, Bultynck G, Parys JB (2015) The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel. Biochim Biophys Acta 1853:1992–2005PubMedCrossRefGoogle Scholar
  247. Vilner BJ, John CS, Bowen WD (1995) Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res 55:408–413PubMedGoogle Scholar
  248. Voos W, Röttgers K (2002) Molecular chaperones as essential mediators of mitochondrial biogenesis. Biochim Biophys Acta 1592:51–62PubMedCrossRefGoogle Scholar
  249. Wadhwa R, Pereira-Smith OM, Reddel RR, Sugimoto Y, Mitsui Y, Kaul SC (1995) Correlation between complementation group for immortality and the cellular distribution of mortalin. Exp Cell Res 216:101–106PubMedCrossRefGoogle Scholar
  250. Wadhwa R, Takano S, Robert M, Yoshida A, Nomura H, Reddel RR, Mitsui Y, Kaul SC (1998) Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J Biol Chem 273:29586–29591PubMedCrossRefGoogle Scholar
  251. Wadhwa R, Taira K, Kaul SC (2002a) An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where? Cell Stress Chaperones 7:309–316PubMedPubMedCentralCrossRefGoogle Scholar
  252. Wadhwa R, Yaguchi T, Hasan MK, Mitsui Y, Reddel RR, Kaul SC (2002b) Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. Exp Cell Res 274:246–253PubMedCrossRefGoogle Scholar
  253. Wagner LE, Joseph SK, Yule DI (2008) Regulation of single inositol 1,4,5-trisphosphate receptor channel activity by protein kinase A phosphorylation. J Physiol 586:3577–3596PubMedCrossRefGoogle Scholar
  254. Wang B, Rouzier R, Albarracin CT, Sahin A, Wagner P, Yang Y, Smith TL, Meric-Bernstam F, Marcelo Aldaz C, Marcelo AC et al (2004) Expression of sigma 1 receptor in human breast cancer. Breast Cancer Res Treat 87:205–214PubMedCrossRefGoogle Scholar
  255. Wang W, Xie Q, Zhou X, Yao J, Zhu X, Huang P, Zhang L, Wei J, Xie H, Zhou L et al (2015) Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells. Cancer Lett 358:47–58PubMedCrossRefGoogle Scholar
  256. Wei C, Wang X, Chen M, Ouyang K, Song L-S, Cheng H (2009) Calcium flickers steer cell migration. Nature 457:901–905PubMedCrossRefGoogle Scholar
  257. Wei C, Wang X, Zheng M, Cheng H (2012) Calcium gradients underlying cell migration. Curr Opin Cell Biol 24:254–261PubMedCrossRefGoogle Scholar
  258. Weisthal S, Keinan N, Ben-Hail D, Arif T, Shoshan-Barmatz V (2014) Ca2+-mediated regulation of VDAC1 expression levels is associated with cell death induction. Biochim Biophys Acta 1843:2270–2281PubMedCrossRefGoogle Scholar
  259. Werneburg NW, Bronk SF, Guicciardi ME, Thomas L, Dikeakos JD, Thomas G, Gores GJ (2012) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein-induced lysosomal translocation of proapoptotic effectors is mediated by phosphofurin acidic cluster sorting protein-2 (PACS-2). J Biol Chem 287:24427–24437PubMedPubMedCentralCrossRefGoogle Scholar
  260. White C, Li C, Yang J, Petrenko NB, Madesh M, Thompson CB, Foskett JK (2005) The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R. Nat Cell Biol 7:1021–1028PubMedPubMedCentralCrossRefGoogle Scholar
  261. Whitehurst AW (2014) Cause and consequence of cancer/testis antigen activation in cancer. Annu Rev Pharmacol Toxicol 54:251–272PubMedCrossRefGoogle Scholar
  262. Whitehurst AW, Bodemann BO, Cardenas J, Ferguson D, Girard L, Peyton M, Minna JD, Michnoff C, Hao W, Roth MG et al (2007) Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446:815–819PubMedCrossRefGoogle Scholar
  263. Wiel C, Lallet-Daher H, Gitenay D, Gras B, Le Calvé B, Augert A, Ferrand M, Prevarskaya N, Simonnet H, Vindrieux D et al (2014) Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence. Nat Commun 5:3792PubMedCrossRefGoogle Scholar
  264. Williams A, Hayashi T, Wolozny D, Yin B, Su T-C, Betenbaugh MJ, Su T-P (2016) The non-apoptotic action of Bcl-xL: regulating Ca2+ signaling and bioenergetics at the ER-mitochondrion interface. J Bioenerg Biomembr 48:211–225PubMedCrossRefGoogle Scholar
  265. Wilson JE (2003) Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol 206:2049–2057PubMedCrossRefGoogle Scholar
  266. Wu P-K, Hong S-K, Veeranki S, Karkhanis M, Starenki D, Plaza JA, Park J-I (2013) A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol Cell Biol 33:4051–4067PubMedPubMedCentralCrossRefGoogle Scholar
  267. Wu C-H, Lin Y-W, Wu T-F, Ko J-L, Wang P-H (2016a) Clinical implication of voltage-dependent anion channel 1 in uterine cervical cancer and its action on cervical cancer cells. Oncotarget 7:4210–4225PubMedCrossRefGoogle Scholar
  268. Wu Y, Zhou D, Xu X, Zhao X, Huang P, Zhou X, Song W, Guo H, Wang W, Zheng S (2016b) Clinical significance of mitofusin-2 and its signaling pathways in hepatocellular carcinoma. World J Surg Oncol 14:179PubMedPubMedCentralCrossRefGoogle Scholar
  269. Xie Q, Su J, Jiao B, Shen L, Ma L, Qu X, Yu C, Jiang X, Xu Y, Sun L (2016) ABT737 reverses cisplatin resistance by regulating ER-mitochondria Ca2+ signal transduction in human ovarian cancer cells. Int J OncolGoogle Scholar
  270. Xu D, Yi W, Chen Y, Ma L, Wang J, Yu G (2014) Overexpression of Sig1R is closely associated with tumor progression and poor outcome in patients with hilar cholangiocarcinoma. Med Oncol Northwood Lond Engl 31:261CrossRefGoogle Scholar
  271. Yang L, Li H, Jiang Y, Zuo J, Liu W (2013) Inhibition of mortalin expression reverses cisplatin resistance and attenuates growth of ovarian cancer cells. Cancer Lett 336:213–221PubMedCrossRefGoogle Scholar
  272. Yang J, Vais H, Gu W, Foskett JK (2016) Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-xL control of cell viability. Proc Natl Acad Sci USA 113:1953–1962Google Scholar
  273. Yi X, Luk JM, Lee NP, Peng J, Leng X, Guan X-Y, Lau GK, Beretta L, Fan S-T (2008) Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol Cell Proteomics 7:315–325PubMedCrossRefGoogle Scholar
  274. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891PubMedCrossRefGoogle Scholar
  275. Yoshikawa F, Iwasaki H, Michikawa T, Furuichi T, Mikoshiba K (1999) Trypsinized cerebellar inositol 1,4,5-trisphosphate receptor. Structural and functional coupling of cleaved ligand binding and channel domains. J Biol Chem 274:316–327PubMedCrossRefGoogle Scholar
  276. Youker RT, Shinde U, Day R, Thomas G (2009) At the crossroads of homoeostasis and disease: roles of the PACS proteins in membrane traffic and apoptosis. Biochem J 421:1–15PubMedPubMedCentralCrossRefGoogle Scholar
  277. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59PubMedCrossRefGoogle Scholar
  278. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) serine phosphorylation of death agonist bad in response to survival factor results in binding to 14-3-3 not BCL-XL. Cell 87:619–628PubMedCrossRefGoogle Scholar
  279. Zhang F, Hamanaka RB, Bobrovnikova-Marjon E, Gordan JD, Dai M-S, Lu H, Simon MC, Diehl JA (2006) Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest. J Biol Chem 281:30036–30045PubMedCrossRefGoogle Scholar
  280. Zhang G-E, Jin H-L, Lin X-K, Chen C, Liu X-S, Zhang Q, Yu J-R (2013) Anti-tumor effects of Mfn2 in gastric cancer. Int J Mol Sci 14:13005–13021PubMedPubMedCentralCrossRefGoogle Scholar
  281. Zhang C, Ding W, Liu Y, Hu Z, Zhu D, Wang X, Yu L, Wang L, Shen H, Zhang W et al (2016a) Proteomics-based identification of VDAC1 as a tumor promoter in cervical carcinoma. Oncotarget 7:52317–52328PubMedPubMedCentralCrossRefGoogle Scholar
  282. Zhang G, Jiang G, Wang C, Zhong K, Zhang J, Xue Q, Li X, Jin H, Li B, Zhang G et al (2016b) Decreased expression of microRNA-320a promotes proliferation and invasion of non-small cell lung cancer cells by increasing VDAC1 expression. Oncotarget 7:49470–49480PubMedPubMedCentralCrossRefGoogle Scholar
  283. Zheng J (2012) Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncol Lett 4:1151–1157PubMedPubMedCentralGoogle Scholar
  284. Zhong F, Harr MW, Bultynck G, Monaco G, Parys JB, De Smedt H, Rong Y-P, Molitoris JK, Lam M, Ryder C et al (2011) Induction of Ca2+ –driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2-IP3 receptor interaction. Blood 117:2924–2934Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Martijn Kerkhofs
    • 1
  • Carlotta Giorgi
    • 2
  • Saverio Marchi
    • 2
  • Bruno Seitaj
    • 1
  • Jan B. Parys
    • 1
  • Paolo Pinton
    • 2
  • Geert Bultynck
    • 1
  • Mart Bittremieux
    • 1
  1. 1.Laboratory Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Instituut (LKI)KU LeuvenLeuvenBelgium
  2. 2.Laboratory for Technologies of Advanced Therapies (LTTA), Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental BiologyUniversity of FerraraFerraraItaly

Personalised recommendations