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Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy

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Abstract

Macroautophagy (Autophagy), an evolutionarily conserved cellular self-digesting process implicated in various physiological and pathological processes, is activated by different stimuli including oxidative stress. Reactive oxygen species (ROS) are involved in autophagy modulation through multiple signaling pathways and transcription regulators. Accumulating data support both a positive and negative role of ROS-modulated autophagy in cancer. As a tumor suppressive mechanism, autophagy induces autophagic cell death and maintains genome stability. Conversely, autophagy may promote cancer development by limiting metabolic stress and supplying high-energetic nutrients. Mitochondrial ROS (mitoROS), the main source of endogenous ROS, serve as essential signal transducers that mediate autophagy, while autophagy can also regulate mitochondrial ROS generation in turn. Here, we untangle the knot between mitochondrial ROS and autophagy, which may be of great significance to solve the conundrum of the inter-conversion between cytoprotective and cytotoxic roles of autophagy; thus providing new insights for current cancer therapies. Whilst, we focus on anti-tumor agents that target mitoROS-regulated autophagy, in the hope of fueling the exploration of more potential novel anti-cancer drugs in the future.

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References

  1. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Eskelinen EL, Saftig P (2008) Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 1793:664–673

    PubMed  Google Scholar 

  3. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368:651–662

    CAS  PubMed  Google Scholar 

  5. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741

    CAS  PubMed  Google Scholar 

  6. Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330:1344–1348

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469:323–335

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Azad MB, Chen Y, Gibson SB (2009) Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Sign 11:777–790

    CAS  Google Scholar 

  9. Essick EE, Sam F (2010) Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer. Oxid Med Cell Longev 3:168–177

    PubMed  PubMed Central  Google Scholar 

  10. Band M, Joel A, Hernandez A, Avivi A (2009) Hypoxia-induced BNIP3 expression and mitophagy: in vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi. FASEB J 23:2327–2335

    CAS  PubMed  Google Scholar 

  11. Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M (2007) Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy 3:614–615

    CAS  PubMed  Google Scholar 

  12. Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17:422–427

    CAS  PubMed  Google Scholar 

  13. Patergnani S, Missiroli S, Marchi S, Giorgi S (2015) Mitochondria-associated endoplasmic reticulum membranes microenvironment: targeting autophagic and apoptotic pathways in cancer therapy. Front Oncol 5:173

    PubMed  PubMed Central  Google Scholar 

  14. Kimmelman AC (2011) The dynamic nature of autophagy in cancer. Genes Dev 25:1999–2010

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H et al (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25:717–729

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli Uzunbas G (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–470

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S et al (2011) Autophagy-deficient mice develop multiple liver tumors. Genes Dev 25:795–800

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen N, Karantza-Wadsworth V (2009) Role and regulation of autophagy in cancer. Biochim Biophys Acta 1793:1516–1523

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78:217–245

    CAS  PubMed  Google Scholar 

  20. Berry DL, Baehrecke EH (2007) Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131:1137–1148

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Frank M, Duvezin-Caubet S, Koob S, Occhipinti A, Jagasia R, Petcherski A et al (2012) Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta 1823:2297–2310

    CAS  PubMed  Google Scholar 

  22. Poillet-Perez L, Despouy G, Delage-Mourroux R, Boyer-Guittaut M (2015) Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol 4:184–192

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Micheal D, Hannelore M, Patrizia A (2010) ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy 6:838–854

    Google Scholar 

  24. Bellot GL, Liu D, Pervaiz S (2013) ROS, autophagy, mitochondria and cancer: Ras, the hidden master? Mitochondrion 13:155–162

    CAS  PubMed  Google Scholar 

  25. Antonenkov VD, Grunau S, Ohlmeier S, Hiltunen JK (2010) Peroxisomes are oxidative organelles. Antioxid Redox Sign 13:525–537

    CAS  Google Scholar 

  26. Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antiox Redox Sign 9:2277–2293

    CAS  Google Scholar 

  27. Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189

    CAS  PubMed  Google Scholar 

  28. Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72:1493–1505

    CAS  PubMed  Google Scholar 

  29. Finkel T (2012) Signal transduction by mitochondrial oxidants. J Biol Chem 287:4434–4440

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Handy DE, Loscalzo J (2012) Redox regulation of mitochondrial function. Antioxid Redox Sign 16:1323–1367

    CAS  Google Scholar 

  31. Li ZY, Yang Y, Ming M, Liu B (2011) Mitochondrial ROS generation for regulation of autophagic pathways in cancer. Biochem Biophys Res Commun 414:5–8

    CAS  PubMed  Google Scholar 

  32. Sabharwal SS, Schumacker PT (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer 14:709–721

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Venditti P, Di Stefano L, Di Meo S (2013) Mitochondrial metabolism of reactive oxygen species. Mitochondrion 13:71–82

    CAS  PubMed  Google Scholar 

  34. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Adam-Vizi V, Chinopoulos C (2006) Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645

    CAS  PubMed  Google Scholar 

  36. Huang J, Klionsky DJ (2007) Autophagy and human disease. Cell Cycle 6:1837–1849

    CAS  PubMed  Google Scholar 

  37. Fader CM, Colombo MI (2009) Autophagy and multivesicular bodies: two closely related partners. Cell Death Differ 16:70–78

    CAS  PubMed  Google Scholar 

  38. Eskelinen EL (2008) New insights into the mechanisms of macroautophagy in mammalian cells. Int Rev Cell Mol Biol 266:207–247

    CAS  PubMed  Google Scholar 

  39. Yoshimori T, Noda T (2008) Toward unraveling membrane biogenesis in mammalian autophagy. Curr Opin Cell Biol 20:401–407

    CAS  PubMed  Google Scholar 

  40. Navarro-Yepes J, Burns M, Anandhan A, Khalimonchuk O, del Razo LM, Quintanilla-Vega B et al (2014) Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid Redox Sign 21:66–85

    CAS  Google Scholar 

  41. Dodson M, Darley-Usmar V, Zhang J (2013) Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med 63:207–221

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Morselli E, Galluzzi L, Kepp O, Vicencio JM, Criollo A, Maiuri MC et al (2009) Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta 1793:1524–1532

    CAS  PubMed  Google Scholar 

  43. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B (2010) Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy 6:322–329

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    CAS  PubMed  Google Scholar 

  45. Petiot A, Ogier Denis E, Blommaart EF, Meijer AJ, Codogno P (2000) Distinct classes of phosphatidylinositol 3-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 275:992–998

    CAS  PubMed  Google Scholar 

  46. Pons DG, Torrens-Mas M, Nadal-Serrano M, Sastre-Serra J, Roca P, Oliver J (2015) The presence of estrogen receptor β modulates the response of breast cancer cells to therapeutic agents. Int J Biochem Cell Biol 66:85–94

    CAS  PubMed  Google Scholar 

  47. Li L, Chen Y, Gibson SB (2013) Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal 25:50–65

    CAS  PubMed  Google Scholar 

  48. Oberstein A, Jeffrey PD, Shi Y (2007) Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Bio Chem 282:13123–13132

    CAS  Google Scholar 

  49. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y et al (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9:1142–1151

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD et al (1998) A protein conjugation system essential for autophagy. Nature 395:395–398

    CAS  PubMed  Google Scholar 

  51. Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T et al (2003) Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12–pg5 conjugate. J Cell Sci 116:1679–1688

    CAS  PubMed  Google Scholar 

  52. Geng J, Klionsky DJ (2008) The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. EMBO Rep 9:859–864

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang K, Klionsky DJ (2011) Mitochondria removal by autophagy. Autophagy 7:297–300

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y et al (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Bio 12:213–223

    CAS  Google Scholar 

  55. Villeneuve NF, Lau A, Zhang DD (2010) Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal 13:1699–1712

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661

    CAS  PubMed  Google Scholar 

  57. Wen X, Wu J, Wang F, Liu B, Huang C, Wei Y (2013) Deconvoluting the role of reactive oxygen species and autophagy in human diseases. Free Radic Biol Med 65:402–410

    CAS  PubMed  Google Scholar 

  58. Planchon SM, Waite KA, Eng C (2008) The nuclear affairs of PTEN. J Cell Sci 121:249–253

    CAS  PubMed  Google Scholar 

  59. Gupta SC, Singh R, Pochampally R, Watabeand K, Mo YY (2014) Acidosis promotes invasiveness of breast cancer cells through ROS–AKT–NF-κB pathway. Oncotarget 5:12070–12082

    PubMed  PubMed Central  Google Scholar 

  60. Shimura T, Sasatani M, Kamiya K, Kawai H, Inaba Y, Kunugita N (2015) Mitochondrial reactive oxygen species perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of PP2A in lowdose irradiated human fibroblasts. Oncotarget 7:3559–3570

    Google Scholar 

  61. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT (2010) ATM activation by oxidative stress. Science 330:517–521

    CAS  PubMed  Google Scholar 

  62. Eisenberg-Lerner A, Kimchi A (2011) PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk. Cell Death Differ 19:788–797

    PubMed  PubMed Central  Google Scholar 

  63. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M et al (2009) DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of Beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 10:285–292

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Tsai YT, Chuang MJ, Tang SH, Wu ST, Chen YC, Sun GH et al (2015) Novel cancer therapeutics with allosteric modulation of the mitochondrial C-Raf-DAPK complex by raf inhibitor combination therapy. Cancer Res 75:3568–3582

    CAS  PubMed  Google Scholar 

  65. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J et al (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29:2570–2581

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bell EL, Emerling BM, Chandel NS (2005) Mitochondrial regulation of oxygen sensing. Mitochondrion 5:322–332

    CAS  PubMed  Google Scholar 

  67. Kang R, Livesey KM, Zeh HJ, Loze MT, Tang D (2010) HMGB1:a novel Beclin 1-binding protein active in autophagy. Autophagy 6:1209–1211

    CAS  PubMed  Google Scholar 

  68. Tang D, Kang R, Livesey KM, Zeh HJ 3rd, Lotze MT (2011) High mobility group box 1 (HMGB1) activates an autophagic response to oxidative stress. Antioxid Redox Sign 15:2185–2195

    CAS  Google Scholar 

  69. Mittal D, Saccheri F, Vénéreau E, Pusterla T, Bianchi ME, Rescigno M (2010) TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells. EMBO J 29:2242–2252

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P et al (2010) Endogenous HMGB1 regulates autophagy. J Cell Biol 190:881–892

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Chew HW, Kartini BI, Sanjiv KY, Jayshree LH, Thomas L, Shazib P (2010) Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One 5:e9996

    Google Scholar 

  72. Ni Z, Wang B, Dai X, Ding W, Yang T, Li X et al (2014) HCC cells with high levels of Bcl-2 are resistant to ABT -737 via activation of the ROS–JNK–autophagy pathway. Free Radic Biol Med 70:194–203

    CAS  PubMed  Google Scholar 

  73. Betin VMS, MacVicar TDB, Parsons SF, Anstee DJ, Lane JD (2012) A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress. Autophagy 8:664–676

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL et al (2009) Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8:1571–1576

    CAS  PubMed  Google Scholar 

  75. Kihara A, Noda T, Ishihara N, Ohsumi Y (2001) Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152:519–530

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Green DR, Levine B (2014) To be or not to be? How selective autophagy and cell death govern cell fate. Cell 157:65–75

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Gibson SB (2010) A matter of balance between life and death: argeting reactive oxygen species (ROS)-induced autophagy for cancer therapy. Autophagy 6:835–837

    CAS  PubMed  Google Scholar 

  78. Czaja MJ (2011) Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology 140:1895–1908

    PubMed  PubMed Central  Google Scholar 

  79. Huett A, Goel G, Xavier RJ (2010) A systems biology viewpoint on autophagy in health and disease. Curr Opin Gastroenterol 26:302–309

    PubMed  Google Scholar 

  80. Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kim MJ, Woo SJ, Yoon CH, Lee JS, An S, Choi YH et al (2011) Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem 286:12924–12932

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T et al (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268

    CAS  PubMed  Google Scholar 

  83. Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT et al (2008) The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell 13:343–354

    CAS  PubMed  Google Scholar 

  84. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S et al (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Gene Dev 21:1621–1635

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10:51–64

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Mazure NM, Pouyssegur J (2010) Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol 22:177–180

    CAS  PubMed  Google Scholar 

  87. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wei H, Wei S, Gan B, Peng X, Zou W, Guan JL (2011) Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Gene Dev 25:1510–1527

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Buchheit CL, Rayavarapu RR, Schafer ZT (2012) The regulation of cancer cell death and metabolism by extracellular matrix attachment. Semin Cell Dev Biol 23:402–411

    CAS  PubMed  Google Scholar 

  90. Nicolas R, Bárbara Borda D, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870

    Google Scholar 

  91. Kenific CM, Thorburn A, Debnath J (2010) Autophagy and metastasis: another double-edged sword. Cur Opin Cell Biol 22:241–245

    CAS  Google Scholar 

  92. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    CAS  PubMed  Google Scholar 

  93. Pavlides S, Vera I, Gandara R, Sneddon S, Pestell RG et al (2012) Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid Redox Signal 16:1264–1284

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhao X, He Y, Chen H (2013) Autophagic tumor stroma: mechanisms and roles in tumor growth and progression. Int J Cancer 132:1–8

    PubMed  Google Scholar 

  95. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R et al (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120

    CAS  PubMed  Google Scholar 

  96. Janku F, McConkey DJ, Hong DS, Kurzrock R (2011) Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 8:528–539

    CAS  PubMed  Google Scholar 

  97. Kawanishi S, Hiraku Y, Pinlaor S, Ma N (2006) Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol Chem 387:365–372

    CAS  PubMed  Google Scholar 

  98. Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal 10:1343–1374

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Bhogal RH, Weston CJ, Curbishley SM, Adams DH, Afford SC (2012) Autophagy: a cyto-protective mechanism which prevents primary human hepatocyte apoptosis during oxidative stress. Autophagy 8:545–558

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY et al (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137:1062–1075

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pan X, Zhang X, Sun H, Zhang J, Yan M, Zhang H (2013) Autophagy inhibition promotes 5-fluorouraci-induced apoptosis by stimulating ROS formation in human non-small cell lung cancer A549 cells. PLoS One 8:e56679

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhai B, Hu F, Jiang X, Xu J, Zhao D, Liu B et al (2014) Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther 13:1589–1598

    CAS  PubMed  Google Scholar 

  103. Dewaele M, Martinet W, Rubio N, Verfaillie T, de Witte PA, Piette J et al (2011) Autophagy pathways activated in response to PDT contribute to cell resistance against ROS damage. J Cell Mol Med 15:1402–1414

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Rubio N, Coupienne I, Di Valentin E, Heirman I, Grooten J, Piette J et al (2012) Spatiotemporal autophagic degradation of oxidatively damaged organelles after photodynamic stress is amplified by mitochondrial reactive oxygen species. Autophagy 8:1312–1324

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Reiners JJ, Agostinis P, Berg K, Oleinick NL, Kessel D (2010) Assessing autophagy in the context of photodynamic therapy. Autophagy 6:7–18

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Chatterjee SJ, Pandey S (2011) Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy. Cancer Biol Ther 11:216–228

    CAS  PubMed  Google Scholar 

  107. Hahm ER, Sakao K, Singh SV (2014) Honokiol activates reactive oxygen species-mediated cytoprotective autophagy in human prostate cancer cells. Prostate 74:1209–1221

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Shigemura K, Arbiser JL, Sun SY, Zayzafoon M, Johnstone PA, Fujisawa M et al (2007) Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer 109:1279–1289

    CAS  PubMed  Google Scholar 

  109. Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY et al (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 6:6656

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang Z, Shi X, Li Y, Zeng X, Fan J, Sun Y et al (2014) Involvement of autophagy in recombinant human arginase-induced cell apoptosis and growth inhibition of malignant melanoma cells. Appl Microbiol Biotechnol 98:2485–2494

    CAS  PubMed  Google Scholar 

  111. Mauldin JP, Zeinali I, Kleypas K, Woo JH, Blackwood RS, Jo CH et al (2012) Recombinant human arginase toxicity in mice is reduced by citrulline supplementation. Transl Oncol 5:26–31

    PubMed  PubMed Central  Google Scholar 

  112. Wilankar C, Khan NM, Checker R, Sharma D, Patwardhan R, Gota V et al (2011) γ-Tocotrienol induces apoptosis in human T cell lymphoma through activation of both intrinsic and extrinsic pathways. Curr Pharm Des 17:2176–2189

    CAS  PubMed  Google Scholar 

  113. Tran AT, Ramalinga M, Kedir H, Clarke R, Kumar D (2014) Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells. Eur J Nutr 54:1–8

    Google Scholar 

  114. Prasanthi K, Susu Z, Vaishali P, Robert S, Satya N, Ritu AJ (2010) Induction of reactive oxygen species-mediated autophagy by a novel microtubule-modulating agent. J Biol Chem 285:18737–18748

    Google Scholar 

  115. Yunha K, Yong-Sook K, Dong EK, Lee JS, Song JH, Kim HG et al (2013) BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy 12:2126–2139

    Google Scholar 

  116. Akimoto M, Iizuka M, Kanematsu R, Yoshida M, Takenaga K (2015) Anticancer effect of ginger extract against pancreatic cancer cells mainly through reactive oxygen species-mediated autotic cell death. PLoS One 10:e0126605

    PubMed  PubMed Central  Google Scholar 

  117. Larocque K, Ovadje P, Djurdjevic S, Mehdi M, Green J, Pandey S (2014) Novel analogue of colchicine induces selective pro-death autophagy and necrosis in human cancer cells. PLoS One 9:e87064

    PubMed  PubMed Central  Google Scholar 

  118. Giammarioli AM, Gambardella L, Barbati C, Pietraforte D, Tinari A, Alberton M et al (2012) Differential effects of the glycolysis inhibitor 2-deoxy-d-glucose on the activity of proapoptotic agents in metastatic melanoma cells, and induction of a cytoprotective autophagic response. Int J Cancer 131:E337–E347

    CAS  PubMed  Google Scholar 

  119. Zhang YH, Wu YL, Tashiro S, Onodera S, Ikejima T (2011) Reactive oxygen species contribute to oridonin-induced apoptosis and autophagy in human cervical carcinoma HeLa cells. Acta Pharmacol Sin 32:1266–1275

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Liu Z, Ouyang L, Peng H, Zhang WZ (2012) Oridonin: targeting programmed cell death pathways as an anti-tumour agent. Cell Prolif 45:499–507

    CAS  PubMed  Google Scholar 

  121. Zang L, He H, Xu Q, Yu Y, Zheng N, Liu W et al (2013) Reactive oxygen species H2O2 and ·OH, but not O2(−) promote oridonin-induced phagocytosis of apoptotic cells by human histocytic lymphoma U937 cells. Int Immunopharmacol 15:414–423

    CAS  PubMed  Google Scholar 

  122. Zhang H, Lei Y, Yuan P, Li L, Luo C, Gao R (2014) ROS-mediated autophagy induced by dysregulation of lipid metabolism plays a protective role in colorectal cancer cells treated with gambogic acid. PLoS One 9:e96418

    PubMed  PubMed Central  Google Scholar 

  123. Hao H, Zhang D, Shi J, Wang Y, Chen L, Guo Y et al (2016) Sorafenib induces autophagic cell death and apoptosis in hepatic stellate cell through the JNK and Akt signaling pathways. Anticancer Drugs 27:192–203

    CAS  PubMed  Google Scholar 

  124. Ke G, Chao C, Yao Z, Yan C, Zebo H, Wenhua L (2012) Autophagy-related gene 7 (ATG7) and reactive oxygen species/extracellular signal-regulated kinase regulate tetrandrine-induced autophagy in human hepatocellular carcinoma. J Biol Chem 287:35576–35588

    Google Scholar 

  125. Selimovic D, Porzig BB, El-Khattouti A, Badura HE, Ahmad M, Ghanjati F et al (2013) Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells. Cell Signal 25:308–318

    CAS  PubMed  Google Scholar 

  126. Hui KF, Yeung PL, Chiang AK (2015) Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib. Oncotarget 7:4454–4467

    Google Scholar 

  127. Toscani D, Palumbo C, Dalla Palma B, Ferretti M, Bolzoni M, Marchica V et al (2015) The proteasome inhibitor, bortezomib, maintains osteocyte viability in multiple myeloma patients by reducing both apoptosis and autophagy: a new function for proteasome inhibitors. J Biol Miner Res. doi:10.1002/jbmr.2741

    Google Scholar 

  128. Gong A, Ye S, Xiong E, Guo W, Zhang Y, Peng W (2013) Autophagy contributes to ING4-induced glioma cell death. Exp Cell Res 319:1714–1723

    CAS  PubMed  Google Scholar 

  129. Raina K, Agarwal C, Wadhwa R, Serkova NJ, Agarwal R (2013) Energy deprivation by silibinin in colorectal cancer cells: a double-edged sword targeting both apoptotic and autophagic machineries. Autophagy 9:697–713

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Jiang K, Wang W, Jin X, Wang Z, Ji Z, Meng G (2015) Silibinin, a natural favonoid, induces autophagy via ROS-dependent mitochondrial dysfunction and loss of ATP involving BNIP3 in human MCF7 breast cancer cells. Oncol Rep 33:2711–2718

    PubMed  PubMed Central  Google Scholar 

  131. Chakrabarti M, Ray SK (2016) Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo. Apoptosis 21:312–328

    CAS  PubMed  Google Scholar 

  132. Yong T, Yakun C, Hongmei J, Daotai N (2015) The role of short-chain fatty acids in orchestrating two types of programmed cell death in colon cancer. Autophagy 7:235–237

    Google Scholar 

  133. Serra C, Sandor NL, Jang H, Lee D, Toraldo G, Guarneri T (2013) The effects of testosterone deprivation and supplementation on proteasomal and autophagy activity in the skeletal muscle of the male mouse: differential effects on high-androgen responder and low-androgen responder muscle groups. Endocrinology 154:4594–4606

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2007) Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J Cell Sci 120:4155–4166

    CAS  PubMed  Google Scholar 

  135. Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB et al (2016) Inhibition of mitochondrial complex II by the anti-cancer agent lonidamine. J Biol Chem 291:42–57

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Dong X, Anna AP, Michelle BM, Eric EK, Ajay BB, Su-Hyeong K (2010) Phenethyl isothiocyanate inhibits oxidative phosphorylation to trigger reactive oxygen species-mediated death of human prostate cancer cell. J Biol Chem 285:26558–26569

    Google Scholar 

  137. Xiao D, Lew KL, Zeng Y, Xiao H, Marynowski SW, Dhir R et al (2006) Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential. Carcinogenesis 27:2223–2234

    CAS  PubMed  Google Scholar 

  138. Lin CS, Wang YC, Huang JL, Huang CC, Chen JY (2012) Autophagy and reactive oxygen species modulate cytotoxicity induced by suppression of ATM kinase activity in head and neck cancer cells. Oral Oncol 48:1152–1158

    CAS  PubMed  Google Scholar 

  139. Wu ZH, Wong ET, Shi Y, Niu J, Chen Z, Miyamoto S et al (2010) ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol Cell 40:75–86

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Xiao D, Powolny AA, Antosiewicz J (2009) Cellular responses to cancer chemopreventive agent D, l-sulforaphane in human prostate cancer cells are initiated by mitochondrial reactive oxygen species. Pharm Res 26:1729–1738

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Conaway CC, Wang CX, Pittman B, Yang YM, Schwartz JE, Tian D et al (2005) Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. Cancer Res 65:8548–8557

    CAS  PubMed  Google Scholar 

  142. Razandi M, Pedram A, Jordan VC, Fuqua S, Levin ER (2013) Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer. Oncogene 32:3274–3285

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Liu B, Cheng Y, Zhang B, Bian HJ, Bao JK (2009) Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. Cancer Lett 275:54–60

    CAS  PubMed  Google Scholar 

  144. Zhang T, Li Y, Park KA, Byun HS, Won M, Jeon J et al (2012) Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis. Autophagy 8:559–576

    CAS  PubMed  Google Scholar 

  145. Yuan G, Yan SF, Xue H, Zhang P, Sun JT, Li GJ (2014) Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo. Biol Chem 289:10607–10619

    CAS  Google Scholar 

  146. Arnab G, Diptiman C, Satabdi D, Surela B, Gopal C (2014) Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis. Biochimie 107:338–349

    Google Scholar 

  147. Nalbandian A, Llewellyn KJ, Nguyen C, Yazdi PG, Kimonis VE (2015) Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy. PLoS One 10:e0122888

    PubMed  PubMed Central  Google Scholar 

  148. Klose J, Stankov MV, Kleine M, Ramackers W, Panayotova-Dimitrova D, Jäger MD et al (2014) Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. PLoS One 9:e95970

    PubMed  PubMed Central  Google Scholar 

  149. Donadelli D, Dando I, Zaniboni T, Costanzo C, Dalla Pozza E, Scupoli MT et al (2011) Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis 2:e152

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Takashi S, Keishi F, Oliver B, Akiyama Y, Moritake K, Shinojima N et al (2009) Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int J Cancer 124:1060–1071

    Google Scholar 

  151. Kanzawa T, Germano IM, Komat T, Ito H, Kondo Y, Kondo S (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 11:448–457

    CAS  PubMed  Google Scholar 

  152. Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I (2003) Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 63:2103–2108

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by grants from the Key Projects of the National Science and Technology Pillar Program (No. 2012BAI30B02), and National Natural Science Foundation of China (Nos. 81160543, 81260628, 81303270 and 81172374).

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    Authors and Affiliations

    1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China

      Yuqian Zhao, Jian Huang & Lingjuan Zhu

    2. School of Basic Medicine Science, Beijing University of Chinese Medicine, Beijing, 100029, China

      Tiange Qu & Hangwu Duan

    3. State Key Laboratory of Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

      Peiqi Wang & Xinyi Li

    4. College of Life Sciences, Sichuan University, Chengdu, 610064, China

      Jiayu Qiang & Zhaokun Xia

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    1. Yuqian Zhao
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    Correspondence to Jian Huang or Lingjuan Zhu.

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    Yuqian Zhao, Tiange Qu, and Peiqi Wang contributed equally to this work.

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    Zhao, Y., Qu, T., Wang, P. et al. Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy. Apoptosis 21, 517–531 (2016). https://doi.org/10.1007/s10495-016-1236-3

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