Skip to main content
SpringerLink
Log in

Regulatory Roles of Autophagy in Cancer

  • Chapter
  • First Online:
Drug Targets in Cellular Processes of Cancer: From Nonclinical to Preclinical Models

  • 407 Accesses

Abstract

Autophagy is an intracellular degradation and recycling system that aids in maintaining the cellular metabolism and homeostasis. Various cellular stresses, including organelle damage, deprivation of nutrients, and accumulation of damaged proteins lead to autophagy that can be associated with cell survival or cell death. Autophagy is initiated with the formation of autophagosome which is a double membrane vesicle. Autophagosome fuses with the lysosome to form autolysosome and deliver cytoplasmic contents that can be degraded or recycled to adapt cellular stressful conditions. Autophagy acts in playing dual roles in tumor suppression and tumor promotion. In addition, autophagy is involved in the maintenance of stemness and homeostasis in cancer stem cells, cancer metastases, and development of resistance to anti-cancer reagents by regulating the expression of many autophagy associated genes. Autophagy modulators such as chloroquine, rapamycin, and their derivatives are used against many cancers, and are in clinical trials. The complete understanding of mechanisms that link autophagy with cancer growth and suppression may aid in the development of promising therapeutics against cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Mizushima N (2005) The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ 12(Suppl 2):1535–1541

    Article  CAS  PubMed  Google Scholar 

  2. Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873

    Article  CAS  PubMed  Google Scholar 

  3. Ameisen JC (2002) On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ 9:367–393

    Article  CAS  PubMed  Google Scholar 

  4. Lorin S, Hamaï A, Mehrpour M, Codogno P (2013) Autophagy regulation and its role in cancer. Semin Cancer Biol 23:361–379

    Article  CAS  PubMed  Google Scholar 

  5. White E (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12:401–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R et al (2009) Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 16:87–93

    Article  CAS  PubMed  Google Scholar 

  7. Botti J, Djavaheri-Mergny M, Pilatte Y, Codogno P (2006) Autophagy signaling and the cogwheels of cancer. Autophagy 2:67–73

    Article  CAS  PubMed  Google Scholar 

  8. Russell RC, Yuan H-X, Guan K-L (2014) Autophagy regulation by nutrient signaling. Cell Res 24:42–57

    Article  CAS  PubMed  Google Scholar 

  9. Mizushima N, Levine B (2010) Autophagy in mammalian development and differentiation. Nat Cell Biol 12:823–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14:207–215

    Article  CAS  PubMed  Google Scholar 

  11. Lim K-H, Staudt LM (2013) Toll-like receptor signaling. Cold Spring Harb Perspect Biol 5:a011247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Salminen A, Kaarniranta K, Kauppinen A (2013) Beclin 1 interactome controls the crosstalk between apoptosis, autophagy and inflammasome activation: impact on the aging process. Ageing Res Rev 12:520–534

    Article  CAS  PubMed  Google Scholar 

  13. Dibble CC, Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15:555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pópulo H, Lopes JM, Soares P (2012) The mTOR signalling pathway in human cancer. Int J Mol Sci 13:1886–1918

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kim YC, Guan K-L (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 125:25–32

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kim J, Kundu M, Viollet B, Guan K-L (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Scott RC, Schuldiner O, Neufeld TP (2004) Role and regulation of starvation-induced autophagy in the drosophila fat body. Dev Cell 7:167–178

    Article  CAS  PubMed  Google Scholar 

  18. Martina JA, Chen Y, Gucek M, Puertollano R (2012) MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8:903–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Torii S, Yoshida T, Arakawa S, Honda S, Nakanishi A, Shimizu S (2016) Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy. EMBO Rep 17:1552–1564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Itakura E, Kishi C, Inoue K, Mizushima N (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19:5360–5372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ktistakis NT, Tooze SA (2016) Digesting the expanding mechanisms of autophagy. Trends Cell Biol 26:624–635

    Article  CAS  PubMed  Google Scholar 

  22. Shen Y, Li D-D, Wang L-L, Deng R, Zhu X-F (2008) Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy 4:1067–1068

    Article  CAS  PubMed  Google Scholar 

  23. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676

    Article  CAS  PubMed  Google Scholar 

  24. Yue Z, Jin S, Yang C, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100:15077–15082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Furuya D, Tsuji N, Yagihashi A, Watanabe N (2005) Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 307:26–40

    Article  CAS  PubMed  Google Scholar 

  26. Sun Y, Liu J-H, Jin L, Lin S-M, Yang Y, Sui Y-X et al (2010) Over-expression of the Beclin1 gene upregulates chemosensitivity to anti-cancer drugs by enhancing therapy-induced apoptosis in cervix squamous carcinoma CaSki cells. Cancer Lett 294:204–210

    Article  CAS  PubMed  Google Scholar 

  27. Oba M, Yano S, Shuto T, Suico MA, Eguma A, Kai H (2008) IFN-gamma down-regulates Hsp27 and enhances hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo. Int J Oncol 32:1317–1324

    CAS  PubMed  Google Scholar 

  28. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T et al (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036

    Article  CAS  PubMed  Google Scholar 

  29. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I et al (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Mariño G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, López-Otín C (2007) Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 282:18573–18583

    Article  PubMed  Google Scholar 

  32. Filomeni G, De Zio D, Cecconi F (2015) Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ 22:377–388

    Article  CAS  PubMed  Google Scholar 

  33. Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O et al (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol 193:275–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li L, Shen C, Nakamura E, Ando K, Signoretti S, Beroukhim R et al (2013) SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer. Cancer Cell 24:738–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu D, Zhou J, Zhao J, Jiang G, Zhang X, Zhang Y et al (2019) ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling. J Cell Physiol 234:8899–8907

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Strohecker AM, White E (2014) Targeting mitochondrial metabolism by inhibiting autophagy in BRAF-driven cancers. Cancer Discov 4:766–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Strohecker AM, Guo JY, Karsli-Uzunbas G, Price SM, Chen GJ, Mathew R et al (2013) Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E–driven lung tumors. Cancer Discov 3:1272–1285

    Article  CAS  PubMed  Google Scholar 

  41. Wei H, Wei S, Gan B, Peng X, Zou W, Guan J-L (2011) Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev 25:1510–1527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kumar G, Tuli HS, Mittal S, Shandilya JK, Tiwari A, Sandhu SS (2015) Isothiocyanates: a class of bioactive metabolites with chemopreventive potential. Tumor Biol 36:4005–4016

    Article  CAS  Google Scholar 

  43. Daskalaki I, Gkikas I, Tavernarakis N (2018) Hypoxia and selective autophagy in cancer development and therapy. Front Cell Dev Biol 6:104

    Article  PubMed  PubMed Central  Google Scholar 

  44. Vaupel P, Mayer A (2005) Hypoxia and anemia: effects on tumor biology and treatment resistance. Transfus Clin Biol 12:5–10

    Article  PubMed  Google Scholar 

  45. Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5:378–389

    Article  PubMed  PubMed Central  Google Scholar 

  46. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713

    Article  CAS  PubMed  Google Scholar 

  47. Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128:2527–2535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14:611–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hamurcu Z, Delibaşı N, Geçene S, Şener EF, Dönmez-Altuntaş H, Özkul Y et al (2018) Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of cyclin-D1 and uPAR/integrin β1/Src signaling in triple negative breast cancer cells. J Cancer Res Clin Oncol Germany 144:415–430

    Article  CAS  Google Scholar 

  51. Liu H, He Z, von Rütte T, Yousefi S, Hunger RE, Simon H-U (2013) Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci Transl Med 5:202ra123

    Article  PubMed  CAS  Google Scholar 

  52. Hashimoto I, Koizumi K, Tatematsu M, Minami T, Cho S, Takeno N et al (2008) Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer 44:1022–1029

    Article  CAS  PubMed  Google Scholar 

  53. Vanharanta S, Massagué J (2013) Origins of metastatic traits. Cancer Cell 24:410–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Guadamillas MC, Cerezo A, Del Pozo MA (2011) Overcoming anoikis--pathways to anchorage-independent growth in cancer. J Cell Sci 124:3189–3197

    Article  CAS  PubMed  Google Scholar 

  55. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    Article  CAS  PubMed  Google Scholar 

  56. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890

    Article  CAS  PubMed  Google Scholar 

  58. Catalano M, D’Alessandro G, Lepore F, Corazzari M, Caldarola S, Valacca C et al (2015) Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. Mol Oncol 9:1612–1625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen Z, Jiang Q, Zhu P, Chen Y, Xie X, Du Z et al (2019) NPRL2 enhances autophagy and the resistance to Everolimus in castration-resistant prostate cancer. Prostate 79:44–53

    Article  CAS  PubMed  Google Scholar 

  60. Xiao X, Wang W, Li Y, Yang D, Li X, Shen C et al (2018) HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma. J Exp Clin Cancer Res 37:201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Kashyap D, Mondal R, Tuli HS, Kumar G, Sharma AK (2016) Molecular targets of gambogic acid in cancer: recent trends and advancements. Tumour Biol 37:12915–12925

    Article  CAS  PubMed  Google Scholar 

  62. Mittal S, Rajala MS (2020) Heat shock proteins as biomarkers of lung cancer. Cancer Biol Ther 21(6):477–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Malet-Martino M, Jolimaitre P, Martino R (2002) The prodrugs of 5-fluorouracil. Curr Med Chem Anticancer Agents 2:267–310

    Article  CAS  PubMed  Google Scholar 

  64. Park JM, Huang S, Wu T-T, Foster NR, Sinicrope FA (2013) Prognostic impact of Beclin 1, p62/sequestosome 1 and LC3 protein expression in colon carcinomas from patients receiving 5-fluorouracil as adjuvant chemotherapy. Cancer Biol Ther 14:100–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sui X, Kong N, Wang X, Fang Y, Hu X, Xu Y et al (2014) JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy. Sci Rep 4:4694

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Liang X, Tang J, Liang Y, Jin R, Cai X (2014) Suppression of autophagy by chloroquine sensitizes 5-fluorouracil-mediated cell death in gallbladder carcinoma cells. Cell Biosci 4:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang J, Wu GS (2014) Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem 289:17163–17173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bao L, Jaramillo MC, Zhang Z, Zheng Y, Yao M, Zhang DD et al (2015) Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells. Mol Med Rep 11:91–98

    Article  CAS  PubMed  Google Scholar 

  69. Cheng CY, Liu JC, Wang JJ, Li YH, Pan J, Zhang YR (2017) Autophagy inhibition increased the anti-tumor effect of cisplatin on drug-resistant esophageal cancer cells. J Biol Regul Homeost Agents 31:645–652

    CAS  PubMed  Google Scholar 

  70. Zhu L, Du H, Shi M, Chen Z, Hang J (2013) ATG7 deficiency promote apoptotic death induced by Cisplatin in human esophageal squamous cell carcinoma cells. Bull Cancer 100:15–21

    PubMed  Google Scholar 

  71. Liu D, Yang Y, Liu Q, Wang J (2011) Inhibition of autophagy by 3-MA potentiates cisplatin-induced apoptosis in esophageal squamous cell carcinoma cells. Med Oncol 28:105–111

    Article  PubMed  CAS  Google Scholar 

  72. Ertmer A, Huber V, Gilch S, Yoshimori T, Erfle V, Duyster J et al (2007) The anticancer drug imatinib induces cellular autophagy. Leukemia 21:936–942

    Article  CAS  PubMed  Google Scholar 

  73. Levy JMM, Thorburn A (2011) Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacol Ther 131:130–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10

    Article  PubMed  CAS  Google Scholar 

  75. Parekh VV, Wu L, Boyd KL, Williams JA, Gaddy JA, Olivares-Villagómez D et al (2013) Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps34. J Immunol 190:5086–5101

    Article  CAS  PubMed  Google Scholar 

  76. Bronietzki AW, Schuster M, Schmitz I (2015) Autophagy in T-cell development, activation and differentiation. Immunol Cell Biol 93:25–34

    Article  CAS  PubMed  Google Scholar 

  77. Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N et al (2009) The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. J Immunol 182:3510–3521

    Article  CAS  PubMed  Google Scholar 

  78. Islam F, Qiao B, Smith RA, Gopalan V, Lam AK-Y (2015) Cancer stem cell: fundamental experimental pathological concepts and updates. Exp Mol Pathol 98:184–191

    Article  CAS  PubMed  Google Scholar 

  79. Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012

    Article  CAS  PubMed  Google Scholar 

  80. Pan H, Cai N, Li M, Liu G-H, Izpisua Belmonte JC (2013) Autophagic control of cell “stemness”. EMBO Mol Med 5:327–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hou J, Han Z, Jing Y, Yang X, Zhang S, Sun K et al (2013) Autophagy prevents irradiation injury and maintains stemness through decreasing ROS generation in mesenchymal stem cells. Cell Death Dis 4:e844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sharif T, Martell E, Dai C, Kennedy BE, Murphy P, Clements DR et al (2017) Autophagic homeostasis is required for the pluripotency of cancer stem cells. Autophagy 13:264–284

    Article  CAS  PubMed  Google Scholar 

  83. Zhao Y, Huang Q, Yang J, Lou M, Wang A, Dong J et al (2010) Autophagy impairment inhibits differentiation of glioma stem/progenitor cells. Brain Res 1313:250–258

    Article  CAS  PubMed  Google Scholar 

  84. Huang X, Bai H-M, Chen L, Li B, Lu Y-C (2010) Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J Clin Neurosci 17:1515–1519

    Article  CAS  PubMed  Google Scholar 

  85. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Vellon L, Menendez JA (2011) Autophagy positively regulates the CD44(+) CD24(−/low) breast cancer stem-like phenotype. Cell Cycle 10:3871–3885

    Article  PubMed  CAS  Google Scholar 

  86. Lee JH, Yun CW, Han Y-S, Kim S, Jeong D, Kwon HY et al (2018) Melatonin and 5-fluorouracil co-suppress colon cancer stem cells by regulating cellular prion protein-Oct4 axis. J Pineal Res 65:e12519

    Article  PubMed  CAS  Google Scholar 

  87. Morel E, Mehrpour M, Botti J, Dupont N, Hamaï A, Nascimbeni AC et al (2017) Autophagy: a druggable process. Annu Rev Pharmacol Toxicol 57:375–398

    Article  CAS  PubMed  Google Scholar 

  88. Eritja N, Chen B-J, Rodríguez-Barrueco R, Santacana M, Gatius S, Vidal A et al (2017) Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer. Autophagy 13:608–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Belounis A, Nyalendo C, Le Gall R, Imbriglio TV, Mahma M, Teira P et al (2016) Autophagy is associated with chemoresistance in neuroblastoma. BMC Cancer 16:891

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Xiong L, Liu Z, Ouyang G, Lin L, Huang H, Kang H et al (2017) Autophagy inhibition enhances photocytotoxicity of Photosan-II in human colorectal cancer cells. Oncotarget 8:6419–6432

    Article  PubMed  Google Scholar 

  91. Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS et al (2010) FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15:428–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F (2013) Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res 73:1449–1453

    Article  CAS  PubMed  Google Scholar 

  93. Anandappa G, Hollingdale A, Eisen T (2010) Everolimus - a new approach in the treatment of renal cell carcinoma. Cancer Manag Res 2:61–70

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Njaria PM, Okombo J, Njuguna NM, Chibale K (2015) Chloroquine-containing compounds: a patent review (2010 - 2014). Expert Opin Ther Pat 25:1003–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Redmann M, Benavides GA, Berryhill TF, Wani WY, Ouyang X, Johnson MS et al (2017) Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons. Redox Biol 11:73–81

    Article  CAS  PubMed  Google Scholar 

  96. Manic G, Obrist F, Kroemer G, Vitale I, Galluzzi L (2014) Chloroquine and hydroxychloroquine for cancer therapy. Mol Cell Oncol 1:e29911

    Article  PubMed  PubMed Central  Google Scholar 

  97. Lin Y-C, Lin J-F, Wen S-I, Yang S-C, Tsai T-F, Chen H-E et al (2017) Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis. Kaohsiung J Med Sci 33:215–223

    Article  PubMed  Google Scholar 

  98. Frieboes HB, Huang JS, Yin WC, McNally LR (2014) Chloroquine-mediated cell death in metastatic pancreatic adenocarcinoma through inhibition of autophagy. JOP 15:189–197

    PubMed  Google Scholar 

  99. Feng X, Li L, Jiang H, Jiang K, Jin Y, Zheng J (2014) Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy. Biochem Biophys Res Commun 444:376–381

    Article  CAS  PubMed  Google Scholar 

  100. Jia G, Kong R, Ma Z-B, Han B, Wang Y-W, Pan S-H et al (2014) The activation of c-Jun NH 2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells. J Exp Clin Cancer Res 33:8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Hu W, Chen S-S, Zhang J-L, Lou X-E, Zhou H-J (2014) Dihydroartemisinin induces autophagy by suppressing NF-κB activation. Cancer Lett 343:239–248

    Article  CAS  PubMed  Google Scholar 

  102. Ganguli A, Choudhury D, Datta S, Bhattacharya S, Chakrabarti G (2014) Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis. Biochimie 107:338–349

    Article  CAS  PubMed  Google Scholar 

  103. Jiang F, Zhou J, Zhang D, Liu M, Chen Y (2018) Artesunate induces apoptosis and autophagy in HCT116 colon cancer cells, and autophagy inhibition enhances the artesunate-induced apoptosis. Int J Mol Med 42:1295–1304

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang ZC, Liu Y, Wang H, Han QK, Lu C (2017) Research on the relationship between artesunate and Raji cell autophagy and apoptosis of Burkitt’s lymphoma and its mechanism. Eur Rev Med Pharmacol Sci 21:2238–2243

    PubMed  Google Scholar 

  105. Berte N, Lokan S, Eich M, Kim E, Kaina B (2016) Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence. Oncotarget 7:67235

    Article  PubMed  PubMed Central  Google Scholar 

  106. Chen K, Shou L-M, Lin F, Duan W-M, Wu M-Y, Xie X et al (2014) Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells. Anti-Cancer Drugs 25:652–662

    PubMed  Google Scholar 

  107. Shinojima N, Yokoyama T, Kondo Y, Kondo S (2007) Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3:635–637

    Article  CAS  PubMed  Google Scholar 

  108. Lee YJ, Kim N-Y, Suh Y-A, Lee C (2011) Involvement of ROS in curcumin-induced autophagic cell death. Korean J Physiol Pharmacol 15:1–7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Li B, Takeda T, Tsuiji K, Wong TF, Tadakawa M, Kondo A et al (2013) Curcumin induces cross-regulation between autophagy and apoptosis in uterine leiomyosarcoma cells. Int J Gynecol Cancer 23:803–808

    Article  PubMed  Google Scholar 

  110. Masuelli L, Benvenuto M, Di Stefano E, Mattera R, Fantini M, De Feudis G et al (2017) Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line. Oncotarget 8:34405

    Article  PubMed  PubMed Central  Google Scholar 

  111. Kumar G, Mittal S, Sak K, Tuli HS (2016) Molecular mechanisms underlying chemopreventive potential of curcumin: current challenges and future perspectives. Life Sci 148:313–328

    Article  CAS  PubMed  Google Scholar 

  112. Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y (2007) Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72:29–39

    Article  CAS  PubMed  Google Scholar 

  113. Lee H-W, Jang KSB, Choi HJ, Jo A, Cheong J-H, Chun K-H (2014) Celastrol inhibits gastric cancer growth by induction of apoptosis and autophagy. BMB Rep 47:697

    Article  PubMed  PubMed Central  Google Scholar 

  114. Boridy S, Le PU, Petrecca K, Maysinger D (2014) Celastrol targets proteostasis and acts synergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells. Cell Death Dis 5:e1216–e1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Li HY, Zhang J, Sun LL, Li BH, Gao HL, Xie T et al (2015) Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study. Cell Death Dis 6:e1604–e1604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhao X, Gao S, Ren H, Huang H, Ji W, Hao J (2014) Inhibition of autophagy strengthens celastrol-induced apoptosis in human pancreatic cancer in vitro and in vivo models. Curr Mol Med 14:555–563

    Article  PubMed  CAS  Google Scholar 

  117. Guo J, Huang X, Wang H, Yang H (2015) Celastrol induces autophagy by targeting AR/miR-101 in prostate cancer cells. PLoS One 10:e0140745

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Rowinsky EK, Donehower RC (1995) Paclitaxel (taxol). N Engl J Med 332:1004–1014

    Article  CAS  PubMed  Google Scholar 

  119. Notte A, Ninane N, Arnould T, Michiels C (2013) Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells: role of autophagy and JNK activation. Cell Death Dis 4:e638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Xi G, Hu X, Wu B, Jiang H, Young CYF, Pang Y et al (2011) Autophagy inhibition promotes paclitaxel-induced apoptosis in cancer cells. Cancer Lett 307:141–148

    Article  CAS  PubMed  Google Scholar 

  121. Veldhoen RA, Banman SL, Hemmerling DR, Odsen R, Simmen T, Simmonds AJ et al (2013) The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene 32:736–746

    Article  CAS  PubMed  Google Scholar 

  122. Li Q, Yue Y, Chen L, Xu C, Wang Y, Du L et al (2018) Resveratrol sensitizes carfilzomib-induced apoptosis via promoting oxidative stress in multiple myeloma cells. Front Pharmacol 9:334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Tomas-Hernández S, Blanco J, Rojas C, Roca-Martínez J, Ojeda-Montes MJ, Beltrán-Debón R et al (2018) Resveratrol potently counteracts quercetin starvation-induced autophagy and sensitizes HepG2 cancer cells to apoptosis. Mol Nutr Food Res 62:1700610

    Article  CAS  Google Scholar 

  124. Liu Q, Fang Q, Ji S, Han Z, Cheng W, Zhang H (2018) Resveratrol-mediated apoptosis in renal cell carcinoma via the p53/AMP-activated protein kinase/mammalian target of rapamycin autophagy signaling pathway. Mol Med Rep 17:502–508

    CAS  PubMed  Google Scholar 

  125. Back JH, Zhu Y, Calabro A, Queenan C, Kim AS, Arbesman J et al (2012) Resveratrol-mediated downregulation of Rictor attenuates autophagic process and suppresses UV-induced skin carcinogenesis. Photochem Photobiol 88:1165–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Puissant A, Robert G, Fenouille N, Luciano F, Cassuto J-P, Raynaud S et al (2010) Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res 70:1042–1052

    Article  CAS  PubMed  Google Scholar 

  127. Tiwari RV, Parajuli P, Sylvester PW (2014) γ-Tocotrienol-induced autophagy in malignant mammary cancer cells. Exp Biol Med 239:33–44

    Article  CAS  Google Scholar 

  128. Tiwari RV, Parajuli P, Sylvester PW (2015) Synergistic anticancer effects of combined γ-tocotrienol and oridonin treatment is associated with the induction of autophagy. Mol Cell Biochem 408:123–137

    Article  CAS  PubMed  Google Scholar 

  129. Jang Y, Rao X, Jiang Q (2017) Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment. J Nutr Biochem 46:49–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Tran AT, Ramalinga M, Kedir H, Clarke R, Kumar D (2015) Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells. Eur J Nutr 54:265–272

    Article  CAS  PubMed  Google Scholar 

  131. Pazhouhi M, Sariri R, Rabzia A, Khazaei M (2016) Thymoquinone synergistically potentiates temozolomide cytotoxicity through the inhibition of autophagy in U87MG cell line. Iran J Basic Med Sci 19:890

    PubMed  PubMed Central  Google Scholar 

  132. Racoma IO, Meisen WH, Wang Q-E, Kaur B, Wani AA (2013) Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One 8:e72882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Chu S-C, Hsieh Y-S, Yu C-C, Lai Y-Y, Chen P-N (2014) Thymoquinone induces cell death in human squamous carcinoma cells via caspase activation-dependent apoptosis and LC3-II activation-dependent autophagy. PLoS One 9:e101579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Shin SW, Kim SY, Park J-W (2012) Autophagy inhibition enhances ursolic acid-induced apoptosis in PC3 cells. Biochim Biophys Acta 1823:451–457

    Article  CAS  PubMed  Google Scholar 

  135. Zhao C, Yin S, Dong Y, Guo X, Fan L, Ye M et al (2013) Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells. Autophagy 9:196–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Leng S, Hao Y, Du D, Xie S, Hong L, Gu H et al (2013) Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. Int J Cancer 133:2781–2790

    CAS  PubMed  Google Scholar 

  137. Xavier CPR, Lima CF, Pedro DFN, Wilson JM, Kristiansen K, Pereira-Wilson C (2013) Ursolic acid induces cell death and modulates autophagy through JNK pathway in apoptosis-resistant colorectal cancer cells. J Nutr Biochem 24:706–712

    Article  CAS  PubMed  Google Scholar 

  138. Lewinska A, Adamczyk-Grochala J, Kwasniewicz E, Deregowska A, Wnuk M (2017) Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells. Apoptosis 22:800–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jung J, Seo J, Kim J, Kim JH (2018) Ursolic acid causes cell death in PC-12 cells by inducing apoptosis and impairing autophagy. Anticancer Res 38:847–853

    Article  CAS  PubMed  Google Scholar 

  140. Mendes VIS, Bartholomeusz GA, Ayres M, Gandhi V, Salvador JAR (2016) Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. Eur J Med Chem 123:317–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Egger ME, Huang JS, Yin W, McMasters KM, McNally LR (2013) Inhibition of autophagy with chloroquine is effective in melanoma. J Surg Res 184:274–281

    Article  CAS  PubMed  Google Scholar 

  142. Wang T, Goodall ML, Gonzales P, Sepulveda M, Martin KR, Gately S et al (2015) Synthesis of improved lysomotropic autophagy inhibitors. J Med Chem 58:3025–3035

    Article  CAS  PubMed  Google Scholar 

  143. Mohapatra P, Preet R, Das D, Satapathy SR, Choudhuri T, Wyatt MD et al (2012) Quinacrine-mediated autophagy and apoptosis in colon cancer cells is through a p53- and p21-dependent mechanism. Oncol Res 20:81–91

    Article  PubMed  CAS  Google Scholar 

  144. Liu W, Huang S, Chen Z, Wang H, Wu H, Zhang D (2014) Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: in vitro and in vivo. Pathol Res Pract 210:764–769

    Article  CAS  PubMed  Google Scholar 

  145. Lui A, New J, Ogony J, Thomas S, Lewis-Wambi J (2016) Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells. BMC Cancer 16:487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Sonam Mittal and Gaurav Kumar contributed equally with all other contributors.

Authors and Affiliations

  1. School of Biotechnology, Jawaharlal Nehru University, New Delhi, India

    Sonam Mittal & G. L. Balasubramani

  2. Department of Biochemistry, University of Delhi, New Delhi, India

    Gaurav Kumar & Pradeep Singh Cheema

  3. Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA

    Deepak Parashar & Anjali Geethadevi

  4. Department of Biotechnology, School of Engineering and Technology, Jaipur National University, Jaipur, Rajasthan, India

    Kapilesh Jadhav

  5. Centre for Polymer Technology, Amity School of Applied Sciences, Amity University Haryana, Gurugram, India

    Chandra Mohan Srivastava

  6. Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India

    Hardeep Singh Tuli

Authors
  1. Sonam Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaurav Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepak Parashar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anjali Geethadevi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kapilesh Jadhav
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. L. Balasubramani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pradeep Singh Cheema
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chandra Mohan Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hardeep Singh Tuli
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India

    Hardeep Singh Tuli

Rights and permissions

Reprints and permissions

Copyright information

© 2020 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mittal, S. et al. (2020). Regulatory Roles of Autophagy in Cancer. In: Tuli, H.S. (eds) Drug Targets in Cellular Processes of Cancer: From Nonclinical to Preclinical Models. Springer, Singapore. https://doi.org/10.1007/978-981-15-7586-0_5

Download citation

Publish with us

Policies and ethics

Search

Navigation