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Hsp70: A Cancer Target Inside and Outside the Cell

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Chaperones

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1709))

Abstract

Heat shock protein 70 (Hsp70) is the most ubiquitous stress-inducible chaperone. It accumulates in the cells in response to a wide variety of physiological and environmental insults including anticancer chemotherapy, thus allowing the cell to survive to lethal conditions. Intracellular Hsp70 is viewed as a cytoprotective protein. Indeed, this protein can inhibit key effectors of the apoptotic and autophagy machineries. In cancer cells, the expression of Hsp70 is abnormally high, and Hsp70 may participate in oncogenesis and in resistance to chemotherapy. In rodent models, Hsp70 overexpression increases tumor growth and metastatic potential. Depletion or inhibition of Hsp70 frequently reduces the size of the tumors and can even cause their complete involution. However, HSP70 is also found in the extra-cellular space where it may signal via membrane receptors or endosomes to alter gene transcription and cellular function. Overall, Hsp70 extracellular function is believed to be immnunogenic and the term chaperokine to define the extracellular chaperones such as Hsp70 has been advanced. In this chapter the knowledge to date, as well as some emerging paradigms about the intra- and extra-cellular functions of Hsp70, are presented. The strategies targeting Hsp70 that are being developed in cancer therapy will also be discussed.

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Abbreviations

Hsp:

Heat shock proteins

MDSC:

Myeloid-derived suppressive cells

ROS:

Reactive oxygen species

TLR:

Toll-like receptor

References

  1. Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124

    Article  CAS  PubMed  Google Scholar 

  2. Parcellier A, Gurbuxani S, Schmitt E, Solary E, Garrido C (2003) Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochem Biophys Res Commun 304:505–512

    Article  CAS  PubMed  Google Scholar 

  3. Park HS, Lee JS, Huh SH, Seo JS, Choi EJ (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 20:446–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Garrido C, Gurbuxani S, Ravagnan L, Kroemer G (2001) Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun 286:433–442

    Article  CAS  PubMed  Google Scholar 

  5. Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C (2006) CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 440:551–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ribeil JA, Zermati Y, Vandekerckhove J et al (2007) Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 445:102–105

    Article  CAS  PubMed  Google Scholar 

  7. Frisan E, Vandekerckhove J, de Thonel A et al (2012) Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes. Blood 119:1532–1542

    Article  CAS  PubMed  Google Scholar 

  8. Arlet JB, Ribeil JA, Guillem F et al (2014) HSP70 sequestration by free α-globin promotes ineffective erythropoiesis in β-thalassaemia. Nature 514:242–246

    CAS  PubMed  Google Scholar 

  9. Jego G, Hazoume A, Seigneuric R, Garrido C (2013) Targeting heat shock proteins in cancer. Cancer Lett 332:275–285

    Article  CAS  PubMed  Google Scholar 

  10. Daugaard M, Rohde M, Jäättelä M (2007) The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–3710

    Article  CAS  PubMed  Google Scholar 

  11. Zuiderweg ER, Hightower LE, Gestwicki JE (2017) The remarkable multivalency of the Hsp70 chaperones. Cell Stress Chaperones 22:173–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Voos WA (2003) new connection: chaperones meet a mitochondrial receptor. Mol Cell 11:1–3

    Article  CAS  PubMed  Google Scholar 

  13. Vogel M, Bukau B, Mayer MP (2006) Allosteric regulation of Hsp70 chaperones by a proline switch. Mol Cell 21:359–367

    Article  CAS  PubMed  Google Scholar 

  14. Hennessy F, Nicoll WS, Zimmermann R, Cheetham ME, Blatch GL (2005) Not all J domains are created equal: implications for the specificity of Hsp40-Hsp70 interactions. Protein Sci 14:1697–1709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5:781–791

    Article  CAS  PubMed  Google Scholar 

  16. Colvin TA, Gabai VL, Gong J et al (2014) Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Res 74:4731–4740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dorard C, de Thonel A, Collura A et al (2011) Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nat Med 17:1283–1289

    Article  CAS  PubMed  Google Scholar 

  18. Berthenet K, Bokhari A, Lagrange A et al (2017) HSP110 promotes colorectal cancer growth through STAT3 activation. Oncogene 36:2328–2336

    Article  CAS  PubMed  Google Scholar 

  19. Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125:443–451

    Article  CAS  PubMed  Google Scholar 

  20. Angles F, Castanie-Cornet MP, Slama N et al (2017) Multilevel interaction of the DnaK/DnaJ(HSP70/HSP40) stress-responsive chaperone machine with the central metabolism. Sci Rep 7:41341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marcion G, Seigneuric R, Chavanne E et al (2015) C-terminal amino acids are essential for human heat shock protein 70 dimerization. Cell Stress Chaperones 20:61–72

    Article  CAS  PubMed  Google Scholar 

  22. Schmitt E, Parcellier A, Gurbuxani S et al (2003) Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res 63:8233–8240

    CAS  PubMed  Google Scholar 

  23. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601

    Article  CAS  PubMed  Google Scholar 

  24. Mosser DD, Caron AW, Bourget L et al (2000) The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20:7146–7159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918

    Article  CAS  PubMed  Google Scholar 

  26. Aghdassi A, Phillips P, Dudeja V et al (2007) Heat shock protein 70 increases tumorigenicity and inhibits apoptosis in pancreatic adenocarcinoma. Cancer Res 67:616–625

    Article  CAS  PubMed  Google Scholar 

  27. Gurbuxani S, Bruey JM, Fromentin A et al (2001) Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells. Oncogene 20:7478–7485

    Article  CAS  PubMed  Google Scholar 

  28. Filomenko R, Poirson-Bichat F, Billerey C et al (2002) Atypical protein kinase C zeta as a target for chemosensitization of tumor cells. Cancer Res 62:1815–1821

    CAS  PubMed  Google Scholar 

  29. Gao T, Newton AC (2002) The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. J Biol Chem 277:31585–31592

    Article  CAS  PubMed  Google Scholar 

  30. Hu G, Tang J, Zhang B et al (2006) A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro. J Cell Sci 119:4117–4126

    Article  CAS  PubMed  Google Scholar 

  31. Park HS, Cho SG, Kim CK et al (2002) Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1. Mol Cell Biol 22:7721–7730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee JS, Lee JJ, Seo JS (2005) HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis. J Biol Chem 280:6634–6641

    Article  CAS  PubMed  Google Scholar 

  33. Salehi AH, Morris SJ, Ho WC et al (2006) AEG3482 is an antiapoptotic compound that inhibits Jun kinase activity and cell death through induced expression of heat shock protein 70. Chem Biol 13:213–223

    Article  CAS  PubMed  Google Scholar 

  34. Gabai VL, Yaglom JA, Volloch V et al (2000) Hsp72-mediated suppression of c-Jun N-terminal kinase is implicated in development of tolerance to caspase-independent cell death. Mol Cell Biol 20:6826–6836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Asea A, Rehli M, Kabingu E et al (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  CAS  PubMed  Google Scholar 

  36. Mijatovic T, Mathieu V, Gaussin JF et al (2006) Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers. Neoplasia 8:402–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ran R, Lu A, Zhang L et al (2004) Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa B survival signaling. Genes Dev 18:1466–1481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feng X, Bonni S, Riabowol K (2006) HSP70 induction by ING proteins sensitizes cells to tumor necrosis factor alpha receptor-mediated apoptosis. Mol Cell Biol 26:9244–9255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81:15–27

    Article  CAS  PubMed  Google Scholar 

  40. Gobbo J, Marcion G, Cordonnier M, et al. Restoring anticancer immune response by targeting tumor-derived exosomes with a HSP70 peptide aptamer. J Natl Cancer Inst 2015;108(3)

    Google Scholar 

  41. Akakura S, Yoshida M, Yoneda Y, Horinouchi SA (2001) role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135). J Biol Chem 276:14649–14657

    Article  CAS  PubMed  Google Scholar 

  42. Kondrikov D, Fulton D, Dong Z, Su Y (2015) Heat shock protein 70 prevents hyperoxia-induced disruption of lung endothelial barrier via caspase-dependent and AIF-dependent pathways. PLoS One 10:e0129343

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Schmitt E, Maingret L, Puig PE et al (2006) Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 66:4191–4197

    Article  CAS  PubMed  Google Scholar 

  44. Ruchalski K, Mao H, Li Z et al (2006) Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem 281:7873–7880

    Article  CAS  PubMed  Google Scholar 

  45. Beere HM, Wolf BB, Cain K et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475

    Article  CAS  PubMed  Google Scholar 

  46. Pandey P, Saleh A, Nakazawa A et al (2000) Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 19:4310–4322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sakahira H, Nagata S (2002) Co-translational folding of caspase-activated DNase with Hsp70, Hsp40, and inhibitor of caspase-activated DNase. J Biol Chem 277:3364–3370

    Article  CAS  PubMed  Google Scholar 

  48. Liu QL, Kishi H, Ohtsuka K, Muraguchi A (2003) Heat shock protein 70 binds caspase-activated DNase and enhances its activity in TCR-stimulated T cells. Blood 102:1788–1796

    Article  CAS  PubMed  Google Scholar 

  49. Kotoglou P, Kalaitzakis A, Vezyraki P et al (2009) Hsp70 translocates to the nuclei and nucleoli, binds to XRCC1 and PARP-1, and protects HeLa cells from single-strand DNA breaks. Cell Stress Chaperones 14:391–406

    Article  CAS  PubMed  Google Scholar 

  50. Goel G, Guo M, Ding J et al (2010) Combined effect of tumor necrosis factor (TNF)-alpha and heat shock protein (HSP)-70 in reducing apoptotic injury in hypoxia: a cell culture study. Neurosci Lett 483:162–166

    Article  CAS  PubMed  Google Scholar 

  51. Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC (2001) FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. EMBO J 20:4478–4489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC (2002) The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. J Biol Chem 277:49638–49643

    Article  CAS  PubMed  Google Scholar 

  53. Guo F, Sigua C, Bali P et al (2005) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255

    Article  CAS  PubMed  Google Scholar 

  54. Gabai VL, Mabuchi K, Mosser DD, Sherman MY (2002) Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 22:3415–3424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Candé C, Vahsen N, Garrido C, Kroemer G (2004) Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ 11:591–595

    PubMed  Google Scholar 

  56. Creagh EM, Carmody RJ, Cotter TG (2000) Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells. Exp Cell Res 257:58–66

    Article  CAS  PubMed  Google Scholar 

  57. Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843

    Article  CAS  PubMed  Google Scholar 

  58. Matsumori Y, Hong SM, Aoyama K et al (2005) Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 25:899–910

    Article  CAS  PubMed  Google Scholar 

  59. Lui JC, Kong SK (2007) Heat shock protein 70 inhibits the nuclear import of apoptosis-inducing factor to avoid DNA fragmentation in TF-1 cells during erythropoiesis. FEBS Lett 581:109–117

    Article  CAS  PubMed  Google Scholar 

  60. Kalinowska M, Garncarz W, Pietrowska M, Garrard WT, Widlak P (2005) Regulation of the human apoptotic DNase/RNase endonuclease G: involvement of Hsp70 and ATP. Apoptosis 10:821–830

    Article  CAS  PubMed  Google Scholar 

  61. Hernandez-Tiedra S, Fabrias G, Davila D et al (2016) Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12:2213–2229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jäättelä M, Tschopp J (2003) Caspase-independent cell death in T lymphocytes. Nat Immunol 4:416–423

    Article  PubMed  CAS  Google Scholar 

  63. Nylandsted J, Gyrd-Hansen M, Danielewicz A et al (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200:425–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kirkegaard T, Roth AG, Petersen NH et al (2010) Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463:549–553

    Article  CAS  PubMed  Google Scholar 

  65. Bivik C, Rosdahl I, Ollinger K (2007) Hsp70 protects against UVB induced apoptosis by preventing release of cathepsins and cytochrome c in human melanocytes. Carcinogenesis 28:537–544

    Article  CAS  PubMed  Google Scholar 

  66. Yue Z, Friedman L, Komatsu M, Tanaka K (2009) The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. Biochim Biophys Acta 1793:1496–1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dokladny K, Zuhl MN, Mandell M et al (2013) Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy. J Biol Chem 288:14959–14972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Leu JI, Pimkina J, Frank A, Murphy ME, George DL (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jego G, Lanneau D, De Thonel A et al (2014) Dual regulation of SPI1/PU.1 transcription factor by heat shock factor 1 (HSF1) during macrophage differentiation of monocytes. Leukemia 28:1676–1686

    Article  CAS  PubMed  Google Scholar 

  70. Sashchenko LP, Dukhanina EA, Shatalov YV et al (2007) Cytotoxic T lymphocytes carrying a pattern recognition protein Tag7 can detect evasive, HLA-negative but Hsp70-exposing tumor cells, thereby ensuring FasL/Fas-mediated contact killing. Blood 110:1997–2004

    Article  CAS  PubMed  Google Scholar 

  71. Chalmin F, Ladoire S, Mignot G et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ciocca DR, Frayssinet P, Cuello-Carrión FD (2007) A pilot study with a therapeutic vaccine based on hydroxyapatite ceramic particles and self-antigens in cancer patients. Cell Stress Chaperones 12:33–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Abe M, Manola JB, Oh WK et al (2004) Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer. Clin Prostate Cancer 3:49–53

    Article  CAS  PubMed  Google Scholar 

  74. Ray S, Lu Y, Kaufmann SH et al (2004) Genomic mechanisms of p210BCR-ABL signaling: induction of heat shock protein 70 through the GATA response element confers resistance to paclitaxel-induced apoptosis. J Biol Chem 279:35604–35615

    Article  CAS  PubMed  Google Scholar 

  75. Pocaly M, Lagarde V, Etienne G et al (2007) Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia. Leukemia 21:93–101

    Article  CAS  PubMed  Google Scholar 

  76. Targosz A, Pierzchalski P, Krawiec A et al (2006) Helicobacter pylori inhibits expression of heat shock protein 70 (HSP70) in human epithelial cell line. Importance of Cag A protein. J Physiol Pharmacol 57:265–278

    CAS  PubMed  Google Scholar 

  77. Brondani Da Rocha A, Regner A, Grivicich I et al (2004) Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines. Int J Oncol 25:777–785

    CAS  PubMed  Google Scholar 

  78. Nylandsted J (2009) Extracellular heat shock protein 70: a potential prognostic marker for chronic myeloid leukemia. Leuk Res 33:205–206

    Article  CAS  PubMed  Google Scholar 

  79. Seoane JM, Varela-Centelles PI, Ramirez JR, Cameselle-Teijeiro J, Romero MA, Aguirre JM (2006) Heat shock proteins (HSP70 and HSP27) as markers of epithelial dysplasia in oral leukoplakia. Am J Dermatopathol 28:417–422

    Article  PubMed  Google Scholar 

  80. Takashima M, Kuramitsu Y, Yokoyama Y et al (2006) Proteomic analysis of autoantibodies in patients with hepatocellular carcinoma. Proteomics 6:3894–3900

    Article  CAS  PubMed  Google Scholar 

  81. Cordonnier M, Chanteloup G, Isambert N et al (2017) Exosomes in cancer theranostic: diamonds in the rough. Cell Adhes Migr 11:151–163

    Article  CAS  Google Scholar 

  82. Nylandsted J, Wick W, Hirt UA et al (2002) Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion. Cancer Res 62:7139–7142

    CAS  PubMed  Google Scholar 

  83. Rérole AL, Gobbo J, De Thonel A et al (2011) Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res 71:484–495

    Article  PubMed  CAS  Google Scholar 

  84. Westerheide SD, Kawahara TL, Orton K, Morimoto RI (2006) Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem 281:9616–9622

    Article  CAS  PubMed  Google Scholar 

  85. Phillips PA, Dudeja V, McCarroll JA et al (2007) Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 67:9407–9416

    Article  CAS  PubMed  Google Scholar 

  86. Bae JH, Kim JY, Kim MJ et al (2010) Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70. J Immunother 33:391–401

    Article  CAS  PubMed  Google Scholar 

  87. Antonoff MB, Chugh R, Borja-Cacho D et al (2009) Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery 146:282–290

    Article  PubMed  Google Scholar 

  88. Li M, Wang J, Jing J et al (2009) Synergistic promotion of breast cancer cells death by targeting molecular chaperone GRP78 and heat shock protein 70. J Cell Mol Med 13:4540–4550

    Article  CAS  PubMed  Google Scholar 

  89. Gong Z, Yang J, Yang M et al (2006) Benzo(a)pyrene inhibits expression of inducible heat shock protein 70 in vascular endothelial cells. Toxicol Lett 166:229–236

    Article  CAS  PubMed  Google Scholar 

  90. Banerjee Mustafi S, Chakraborty PK, Raha S (2010) Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70. PLoS One 5:e8719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Gurbuxani S, Schmitt E, Cande C et al (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678

    Article  CAS  PubMed  Google Scholar 

  92. Steele AJ, Prentice AG, Hoffbrand AV et al (2009) 2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells. Blood 114:1217–1225

    Article  CAS  PubMed  Google Scholar 

  93. Balaburski GM, Leu JI, Beeharry N et al (2013) A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res 11:219–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Williamson DS, Borgognoni J, Clay A et al (2009) Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem 52:1510–1513

    Article  CAS  PubMed  Google Scholar 

  95. Asling J, Morrison J, Mutsaers AJ (2016) Targeting HSP70 and GRP78 in canine osteosarcoma cells in combination with doxorubicin chemotherapy. Cell Stress Chaperones 21:1065–1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cavanaugh A, Juengst B, Sheridan K, Danella JF, Williams H (2015) Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer. Oncotarget 6:39821–39838

    Article  PubMed  PubMed Central  Google Scholar 

  97. Kim SH, Kang JG, Kim CS et al (2014) The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis in anaplastic thyroid carcinoma cells. Biochem Biophys Res Commun 454:36–41

    Article  CAS  PubMed  Google Scholar 

  98. Jinwal UK, Miyata Y, Koren J et al (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29:12079–12088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Guo W, Yan L, Yang L et al (2014) Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma. PLoS One 9:e85766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Evans CG, Wisén S, Gestwicki JE (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J Biol Chem 281:33182–33191

    Article  CAS  PubMed  Google Scholar 

  101. Braunstein MJ, Scott SS, Scott CM et al (2011) Antimyeloma effects of the heat shock protein 70 molecular chaperone inhibitor MAL3-101. J Oncol 232037:2011

    Google Scholar 

  102. Wright CM, Seguin SP, Fewell SW et al (2009) Inhibition of Simian Virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen. Virus Res 141:71–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yi F, Regan LA (2008) novel class of small molecule inhibitors of Hsp90. ACS Chem Biol 3:645–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Roodveldt C, Bertoncini CW, Andersson A et al (2009) Chaperone proteostasis in Parkinson’s disease: stabilization of the Hsp70/alpha-synuclein complex by Hip. EMBO J 28:3758–3770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li X, Srinivasan SR, Connarn J, et al. (2013) Analogs of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents. ACS Med Chem Lett 4(11)

    Google Scholar 

  106. Li X, Colvin T, Rauch JN et al (2015) Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer. Mol Cancer Ther 14:642–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Simon EP, Freije CA, Farber BA et al (2015) Transcriptomic characterization of fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci U S A 112:E5916–E5925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Thirunavukarasu D, Shi H, An RNA (2015) aptamer specific to Hsp70-ATP conformation inhibits its ATPase activity independent of Hsp40. Nucleic Acid Ther 25:103–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Collura A, Lagrange A, Svrcek M et al (2014) Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy. Gastroenterology 146:401–11e1

    Article  CAS  PubMed  Google Scholar 

  110. Berthenet K, Boudesco C, Collura A et al (2016) Extracellular HSP110 skews macrophage polarization in colorectal cancer. Oncoimmunology 5:e1170264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Chang YS, Lee LC, Sun FC, Chao CC, Fu HW, Lai YK (2006) Involvement of calcium in the differential induction of heat shock protein 70 by heat shock protein 90 inhibitors, geldanamycin and radicicol, in human non-small cell lung cancer H460 cells. J Cell Biochem 97:156–165

    Article  CAS  PubMed  Google Scholar 

  112. Yun CH, Yoon SY, Nguyen TT et al (2010) Geldanamycin inhibits TGF-beta signaling through induction of Hsp70. Arch Biochem Biophys 495:8–13

    Article  CAS  PubMed  Google Scholar 

  113. Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526

    Article  CAS  PubMed  Google Scholar 

  114. Massey AJ, Williamson DS, Browne H et al (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66:535–545

    Article  CAS  PubMed  Google Scholar 

  115. Rao R, Fiskus W, Ganguly S, Kambhampati S, Bhalla KN (2012) HDAC inhibitors and chaperone function. Adv Cancer Res 116:239–262

    Article  CAS  PubMed  Google Scholar 

  116. Rao R, Fiskus W, Yang Y et al (2008) HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood 112:1886–1893

    Article  CAS  PubMed  Google Scholar 

  117. Bausero MA, Page DT, Osinaga E, Asea A (2004) Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol 25:243–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175:2900–2912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Asea A, Kabingu E, Stevenson MA, Calderwood SK (2000) HSP70 peptidembearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 5:425–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Arispe N, Doh M, Simakova O, Kurganov B, De Maio A (2004) Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability. FASEB J 18:1636–1645

    Article  CAS  PubMed  Google Scholar 

  121. Schilling D, Gehrmann M, Steinem C et al (2009) Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J 23:2467–2477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Asea A (2007) Mechanisms of HSP72 release. J Biosci 32:579–584

    Article  CAS  PubMed  Google Scholar 

  123. Mambula SS, Calderwood SK (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177:7849–7857

    Article  CAS  PubMed  Google Scholar 

  124. Vega VL, Rodríguez-Silva M, Frey T et al (2008) Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 180:4299–4307

    Article  CAS  PubMed  Google Scholar 

  125. Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194

    Article  CAS  PubMed  Google Scholar 

  126. Nicchitta CV (2003) Re-evaluating the role of heat-shock protein-peptide interactions in tumour immunity. Nat Rev Immunol 3:427–432

    Article  CAS  PubMed  Google Scholar 

  127. Castellino F, Boucher PE, Eichelberg K et al (2000) Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 191:1957–1964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Castelli C, Rivoltini L, Rodolfo M, Tazzari M, Belgiovine C, Allavena P (2015) Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies. Cancer Immunol Immunother 64:83–89

    Article  CAS  PubMed  Google Scholar 

  129. Asea A, Kraeft SK, Kurt-Jones EA et al (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442

    Article  CAS  PubMed  Google Scholar 

  130. Kuppner MC, Gastpar R, Gelwer S et al (2001) The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors. Eur J Immunol 31:1602–1609

    Article  CAS  PubMed  Google Scholar 

  131. Specht HM, Ahrens N, Blankenstein C et al (2015) Heat shock protein 70 (Hsp70) peptide activated natural killer (NK) cells for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy (RCTx)—from preclinical studies to a clinical phase II trial. Front Immunol 6:162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Todryk SM, Melcher AA, Dalgleish AG, Vile RG (2000) Heat shock proteins refine the danger theory. Immunology 99:334–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Castelli C, Rivoltini L, Rini F et al (2004) Heat shock proteins: biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol Immunother 53:227–233

    Article  CAS  PubMed  Google Scholar 

  134. Liu J, Cao X (2016) Cellular and molecular regulation of innate inflammatory responses. Cell Mol Immunol 13:711–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    Article  CAS  PubMed  Google Scholar 

  136. Binder RJ, Vatner R, Srivastava P (2004) The heat-shock protein receptors: some answers and more questions. Tissue Antigens 64:442–451

    Article  CAS  PubMed  Google Scholar 

  137. Sondermann H, Becker T, Mayhew M, Wieland F, Hartl FU (2000) Characterization of a receptor for heat shock protein 70 on macrophages and monocytes. Biol Chem 381:1165–1174

    Article  CAS  PubMed  Google Scholar 

  138. Doody AD, Kovalchin JT, Mihalyo MA, Hagymasi AT, Drake CG, Adler AJ (2004) Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J Immunol 172:6087–6092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Singh-Jasuja H, Toes RE, Spee P et al (2000) Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med 191:1965–1974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Flechtner JB, Cohane KP, Mehta S et al (2006) High-affinity interactions between peptides and heat shock protein 70 augment CD8+ T lymphocyte immune responses. J Immunol 177:1017–1027

    Article  CAS  PubMed  Google Scholar 

  141. Habich C, Baumgart K, Kolb H, Burkart V (2002) The receptor for heat shock protein 60 on macrophages is saturable, specific, and distinct from receptors for other heat shock proteins. J Immunol 168:569–576

    Article  CAS  PubMed  Google Scholar 

  142. Vabulas RM, Ahmad-Nejad P, da Costa C et al (2001) Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 276:31332–31339

    Article  CAS  PubMed  Google Scholar 

  143. Bendz H, Ruhland SC, Pandya MJ et al (2007) Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling. J Biol Chem 282:31688–31702

    Article  CAS  PubMed  Google Scholar 

  144. Haug M, Schepp CP, Kalbacher H, Dannecker GE, Holzer U (2007) 70-kDa heat shock proteins: specific interactions with HLA-DR molecules and their peptide fragments. Eur J Immunol 37:1053–1063

    Article  CAS  PubMed  Google Scholar 

  145. Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305

    Article  CAS  PubMed  Google Scholar 

  146. Joly AL, Wettstein G, Mignot G, Ghiringhelli F, Garrido C (2010) Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun 2:238–247

    Article  CAS  PubMed  Google Scholar 

  147. Zhang H, Huang W (2006) Fusion proteins of Hsp70 with tumor-associated antigen acting as a potent tumor vaccine and the C-terminal peptide-binding domain of Hsp70 being essential in inducing antigen-independent anti-tumor response in vivo. Cell Stress Chaperones 11:216–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sanchez-Perez L, Kottke T, Daniels GA et al (2006) Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas. J Immunol 177:4168–4177

    Article  CAS  PubMed  Google Scholar 

  149. Gao B, Tsan MF (2003) Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J Biol Chem 278:22523–22529

    Article  CAS  PubMed  Google Scholar 

  150. Reed RC, Berwin B, Baker JP, Nicchitta CV (2003) GRP94/gp96 elicits ERK activation in murine macrophages. A role for endotoxin contamination in NF-kappa B activation and nitric oxide production. J Biol Chem 278:31853–31860

    Article  CAS  PubMed  Google Scholar 

  151. van Eden W, Spiering R, Broere F, van der Zee RA (2012) case of mistaken identity: HSPs are no DAMPs but DAMPERs. Cell Stress Chaperones 17:281–292

    Article  PubMed  Google Scholar 

  152. Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK (2000) Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 88:232–238

    Article  CAS  PubMed  Google Scholar 

  153. Kottke T, Sanchez-Perez L, Diaz RM et al (2007) Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. Cancer Res 67:11970–11979

    Article  CAS  PubMed  Google Scholar 

  154. Jimbo J, Sato K, Hosoki T et al (2008) Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70. Cancer Sci 99:1427–1434

    Article  CAS  PubMed  Google Scholar 

  155. Toomey D, Conroy H, Jarnicki AG, Higgins SC, Sutton C, Mills KH (2008) Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma. Vaccine 26:3540–3549

    Article  CAS  PubMed  Google Scholar 

  156. Mizukami S, Kajiwara C, Ishikawa H, Katayama I, Yui K, Udono H (2008) Both CD4+ and CD8+ T cell epitopes fused to heat shock cognate protein 70 (hsc70) can function to eradicate tumors. Cancer Sci 99:1008–1015

    Article  CAS  PubMed  Google Scholar 

  157. Liu B, Ye D, Song X et al (2008) A novel therapeutic fusion protein vaccine by two different families of heat shock proteins linked with HPV16 E7 generates potent antitumor immunity and antiangiogenesis. Vaccine 26:1387–1396

    Article  CAS  PubMed  Google Scholar 

  158. Baek KH, Zhang H, Lee BR, Kwon YG, Ha SJ, Shin I (2015) A small molecule inhibitor for ATPase activity of Hsp70 and Hsc70 enhances the immune response to protein antigens. Sci Rep 5:17642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Zeng Y, Chen X, Larmonier N et al (2006) Natural killer cells play a key role in the antitumor immunity generated by chaperone-rich cell lysate vaccination. Int J Cancer 119:2624–2631

    Article  CAS  PubMed  Google Scholar 

  160. Gross C, Hansch D, Gastpar R, Multhoff G (2003) Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biol Chem 384:267–279

    Article  CAS  PubMed  Google Scholar 

  161. Gastpar R, Gehrmann M, Bausero MA et al (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Stangl S, Wortmann A, Guertler U, Multhoff G (2006) Control of metastasized pancreatic carcinomas in SCID/beige mice with human IL-2/TKD-activated NK cells. J Immunol 176:6270–6276

    Article  CAS  PubMed  Google Scholar 

  163. Krause SW, Gastpar R, Andreesen R et al (2004) Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase i trial. Clin Cancer Res 10:3699–3707

    Article  CAS  PubMed  Google Scholar 

  164. Shevtsov MA, Kim AV, Samochernych KA et al (2014) Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children. Onco Targets Ther 7:1071–1081

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgment

This work was supported by grants from the “Ligue Nationale Contre le Cancer”. CG’s group has the label de “La Ligue Contre le Cancer”. The work was also supported by grants from the “Institut National du Cancer”, the “Conseil Regional de Bourgogne”, and the European Regional Development Fund (FEDER); and a French government grant managed by the French National Research Agency (ANR) under the program “Investissements d’Avenir” with reference ANR-11-LABX-0021-01-LipSTIC LabEx.

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Author notes

  1. Gaëtan Jego and Carmen Garrido contributed equally to this work.

Authors and Affiliations

  1. Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France

    Christophe Boudesco, Sebastien Cause, Gaëtan Jego & Carmen Garrido

  2. INSERM, LNC UMR1231, Dijon, France

    Christophe Boudesco, Sebastien Cause, Gaëtan Jego & Carmen Garrido

  3. Equipe Labellisée par la Ligue Nationale Contre le Cancer, INSERM, LNC UMR1231, Dijon, France

    Christophe Boudesco, Sebastien Cause, Gaëtan Jego & Carmen Garrido

  4. LipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France

    Christophe Boudesco, Sebastien Cause, Gaëtan Jego & Carmen Garrido

Authors
  1. Christophe Boudesco
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  2. Sebastien Cause
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  3. Gaëtan Jego
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  4. Carmen Garrido
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Corresponding authors

Correspondence to Gaëtan Jego or Carmen Garrido .

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Editors and Affiliations

  1. Department of Radiation, Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Stuart K. Calderwood

  2. Department of Urology, Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, USA

    Thomas L. Prince

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Boudesco, C., Cause, S., Jego, G., Garrido, C. (2018). Hsp70: A Cancer Target Inside and Outside the Cell. In: Calderwood, S., Prince, T. (eds) Chaperones. Methods in Molecular Biology, vol 1709. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7477-1_27

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  • DOI: https://doi.org/10.1007/978-1-4939-7477-1_27

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  • Print ISBN: 978-1-4939-7476-4

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