Abstract

Autophagy, the process of degradation of unwanted or damaged cell elements, is extremely important for a variety of human diseases, especially cancers. This process influences various stages of initiation and progression of cancer, which is caused by overlapping signaling pathways of autophagy and carcinogenesis. However, due to the complexity of cancer as a systemic disease, the fate of tumor cells is not determined by one signal pathway. Chronic autophagy inhibition leads to tumor promotion, due to instability of the genome, defective cell growth, also as a result of cellular stress. However, increased induction of autophagy may be a mechanism for tumor cell survival in the state of hypoxia, acidosis, as well as under the influence of chemotherapy. Therefore, in the context of cancer development, the process of autophagy should be considered in two directions. Determination of the molecular mechanisms underlying the process of autophagy and its role in the carcinogenesis is a key element of the anticancer strategy. The main objective of modern oncology, which should eventually lead to personalized therapy, is the possibility to predict the response of a particular type of cancer to the used drug. Results of in vitro and in vivo studies show the magnitude of the relationship between changes in the genome, and response to the therapy. This information indicates the mechanism and thereby the target point of the drugs. In this review we focus on the mechanism of autophagy and its role in cancer therapy, which can help to understand the autophagy-cancer relationship and indicate the direction for the design of new drugs with anticancer activity.

References

• 1. Alinari L., Yu B., Christian B.A., Yan F., Shin J., Lapalombella R.,Hertlein E., Lustberg M.E., Quinion C., Zhang X., Lozanski G., MuthusamyN., Prætorius-Ibba M., O’Connor O.A., Goldenberg D.M.,Byrd J.C., Blum K.A., Baiocchi R.A.: Combination anti-CD74 (milatuzumab)and anti-CD20 (rituximab) monoclonal antibody therapyhas in vitro and in vivo activity in mantle cell lymphoma. Blood,2011; 117: 4530-4541
  Google Scholar
• 2. Amaravadi R.K., Winkler J.D.: Lys05: a new lysosomal autophagyinhibitor. Autophagy, 2012; 8: 1383-1384
  Google Scholar
• 3. Anbalagan S., Pires I.M., Blick C., Hill M.A., Ferguson D.J., Chan D.A.,Hammond E.M.: Radiosensitization of renal cell carcinoma in vitrothrough the induction of autophagy. Radiother. Oncol., 2012; 103: 388-393
  Google Scholar
• 4. Banerji V., Gibson S.B.: Targeting metabolism and autophagy inthe context of haematologic malignancies. Int. J. Cell Biol., 2012;2012: 595976
  Google Scholar
• 5. Bellot G., Garcia-Medina R., Gounon P., Chiche J., Roux D.,Pouysségur J., Mazure N.M.: Hypoxia-induced autophagy is mediatedthrough hypoxia-inducible factor induction of BNIP3 andBNIP3L via their BH3 domains. Mol. Cell. Biol., 2009; 29: 2570-2581
  Google Scholar
• 6. Boya P., Kroemer G.: Beclin 1: a BH3-only protein that fails toinduce apoptosis. Oncogene, 2009; 28: 2125-2127
  Google Scholar
• 7. Cao Y., Klionsky D.J.: Physiological functions of Atg6/Beclin 1:a unique autophagy-related protein. Cell Res., 2007; 17: 839-849
  Google Scholar
• 8. Carew J.S., Kelly K.R., Nawrocki S.T.: Autophagy as a target for cancertherapy: new developments. Cancer Manag. Res., 2012; 4: 357-365
  Google Scholar
• 9. Corona G., Rizzolio F., Giordano A., Toffoli G.: Pharmaco-metabolomics:an emerging “omics” tool for the personalization of anticancertreatments and identification of new valuable therapeutictargets. J. Cell. Physiol., 2012; 227: 2827-2831
  Google Scholar
• 10. Czaja J.M.: Functions of autophagy in hepatic and pancreaticphysiology and disease. Gastroenterology, 2011; 140: 1895-1908
  Google Scholar
• 11. Chen N., Debnath J.: Autophagy and tumorigenesis. FEBS Lett.,2010; 584: 1427-1435
  Google Scholar
• 12. Dai Z.J., Gao J., Kang H.F., Ma Y.G., Ma X.B., Lu W.F., Lin S., MaH.B., Wang X.J., Wu W.Y.: Targeted inhibition of mammalian targetof rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinomacells. Drug Des. Devel. Ther., 2013; 7: 149-159
  Google Scholar
• 13. Decuypere J.P., Bultynck G., Parys J.B.: A dual role for Ca2+ inautophagy regulation. Cell Calcium, 2011; 50: 242-250
  Google Scholar
• 14. Erenpreisa J., Huna A., Salmina K., Jackson T.R., Cragg M.S.:Macroautophagy-aided elimination of chromatin: sorting of waste,sorting of fate? Autophagy, 2012; 8: 1877-1881
  Google Scholar
• 15. Fu L.L., Cheng Y., Liu B.: Beclin-1: Autophagic regulator and therapeutictarget in cancer. Int. J. Biochem. Cell Biol., 2013; 45: 921-924
  Google Scholar
• 16. Fujita N., Matsunaga K., Noda T., Yoshimori T.: Molecular mechanismof autophagosome formation in mammalian cells. TanpakushitsuKakusan Koso, 2008; 53 (Suppl. 16): 2106-2110
  Google Scholar
• 17. Gammoh N., Marks P.A., Jiang X.: Curbing autophagy and histonedeacetylases to kill cancer cells. Autophagy, 2012; 8: 1521-1522
  Google Scholar
• 18. García-Mauriño S., Alcaide A., Domínguez C.: Pharmacologicalcontrol of autophagy: therapeutic perspectives in inflammatorybowel disease and colorectal cancer. Curr. Pharm. Des., 2012; 18:3853-3873
  Google Scholar
• 19. Giannopoulou E., Antonacopoulou A., Matsouka P., KalofonosH.P.: Autophagy: novel action of panitumumab in colon cancer. AnticancerRes., 2009; 29: 5077-5082
  Google Scholar
• 20. Giansanti V., Torriglia A., Scovassi A.I.: Conversation betweenapoptosis and autophagy: “Is it your turn or mine?”. Apoptosis,2011; 16: 321-333
  Google Scholar
• 21. Guo X.L., Li D., Sun K., Wang J., Liu Y., Song J.R., Zhao Q.D., ZhangS.S., Deng W.J., Zhao X., Wu M.C., Wei L.X.: Inhibition of autophagyenhances anticancer effects of bevacizumab in hepatocarcinoma. J.Mol. Med., 2013; 91: 473-483
  Google Scholar
• 22. Harrison S.J., Bishton M., Bates S.E., Grant S., Piekarz R.L., JohnstoneR.W., Dai Y., Lee B., Araujo M.E., Prince H.M.: A focus on thepreclinical development and clinical status of the histone deacetylaseinhibitor, romidepsin (depsipeptide, Istodax®) Epigenomics,2012; 4: 571-589
  Google Scholar
• 23. Hay N., Sonenberg N.: Upstream and downstream of mTOR.Genes Dev., 2004; 18: 1926-1945
  Google Scholar
• 24. Jaeger P.A., Wyss-Coray T.: Beclin 1 complex in autophagy andAlzheimer disease. Arch. Neurol., 2010; 67: 1181-1184
  Google Scholar
• 25. Jain K., Paranandi K.S., Sridharan S., Basu A.: Autophagy in breastcancer and its implications for therapy. Am. J. Cancer Res., 2013; 3:251-265
  Google Scholar
• 26. Jia L., Gopinathan G., Sukumar J.T., Gribben J.G.: Blocking autophagyprevents bortezomib-induced NF-κB activation by reducingI-κBα degradation in lymphoma cells. PLoS One, 2012; 7: 32584
  Google Scholar
• 27. Jia W., Pua H.H., Li Q.J., He Y.W.: Autophagy regulates endoplasmicreticulum homeostasis and calcium mobilization in T lymphocytes.J. Immunol., 2011; 186: 1564-1574
  Google Scholar
• 28. Kang R., Zeh H.J., Lotze M.T., Tang D.: The Beclin 1 network regulatesautophagy and apoptosis. Cell Death Differ., 2011; 18: 571-580
  Google Scholar
• 29. Kimmelman A.C.: The dynamic nature of autophagy in cancer.Genes Dev., 2011; 25: 1999-2010
  Google Scholar
• 30. Knizhnik A.V., Roos W.P., Nikolova T., Quiros S., TomaszowskiK.H., Christmann M., Kaina B.: Survival and death strategies in gliomacells: autophagy, senescence and apoptosis triggered by a singletype of temozolomide-induced DNA damage. PLoS One, 2013;8: e55665
  Google Scholar
• 31. Kohli L., Kaza N., Coric T., Byer S.J., Brossier N.M., Klocke B.J.,Bjornsti M.A., Carroll S.L., Roth K.A.: 4-hydroxytamoxifen inducesautophagic death through K-Ras degradation. Cancer Res., 2013;73: 4395-4405
  Google Scholar
• 32. Kost A., Kasprowska D., Labuzek K., Wiaderkiewicz R., GabryelB.: Autophagy in brain ischemia. Postępy Hig. Med. Dośw., 2011;65: 524-533
  Google Scholar
• 33. Koukourakis M.I., Giatromanolaki A., Sivridis E., PitiakoudisM., Gatter K.C., Harris A.L.: Beclin 1 over – and underexpression incolorectal cancer: distinct patterns relate to prognosis and tumourhypoxia. Br. J. Cancer, 2010; 103: 1209-1214
  Google Scholar
• 34. Kuroda J., Shimura Y., Yamamoto-Sugitani M., Sasaki N., TaniwakiM.: Multifaceted mechanisms for cell survival and drug targetingin chronic myelogenous leukemia. Curr. Cancer Drug Targets,2013; 13: 69-79
  Google Scholar
• 35. Lachenmayer A., Toffanin S., Cabellos L., Alsinet C., Hoshida Y.,Villanueva A., Minguez B., Tsai H.W., Ward S.C., Thung S., FriedmanS.L., Llovet J.M.: Combination therapy for hepatocellular carcinoma:additive preclinical efficacy of the HDAC inhibitor panobinostat withsorafenib. J. Hepatol., 2012; 56: 1343-1350
  Google Scholar
• 36. Lee S.J., Kim H.P., Jin Y., Choi A.M., Ryter S.W.: Beclin 1 deficiencyis associated with increased hypoxia-induced angiogenesis. Autophagy,2011; 7: 829-839
  Google Scholar
• 37. Lefranc F., Facchini V., Kiss R.: Proautophagic drugs: a novel meansto combat apoptosis-resistant cancers, with a special emphasison glioblastomas. Oncologist, 2007; 12: 1395-1403
  Google Scholar
• 38. Levine B., Kroemer G.: Autophagy in aging, disease and death:the true identity of a cell death impostor. Cell Death Differ., 2009;16: 1-2
  Google Scholar
• 39. Levine B., Mizushima N., Virgin H.W.: Autophagy in immunityand inflammation. Nature, 2011; 469: 323-335
  Google Scholar
• 40. Levine B., Sinha S., Kroemer G.: Bcl-2 family members: dual regulatorsof apoptosis and autophagy. Autophagy, 2008; 4: 600-606
  Google Scholar
• 41. Li Z., Chen B., Wu Y., Jin F., Xia Y., Liu X.: Genetic and epigeneticsilencing of the beclin 1 gene in sporadic breast tumors. BMCCancer, 2010; 10: 98
  Google Scholar
• 42. Liang C., Feng P., Ku B., Dotan I.,Canaani D., Oh B.H., Jung J.U.:Autophagic and tumour suppressor activity of a novel Beclin1-bindingprotein UVRAG. Nat. Cell Biol., 2006; 8: 688-699
  Google Scholar
• 43. Lin C.I., Whang E.E., Lorch J.H., Ruan D.T.: Autophagic activationpotentiates the antiproliferative effects of tyrosine kinase inhibitorsin medullary thyroid cancer. Surgery, 2012; 152: 1142-1149
  Google Scholar
• 44. Liu B., Cheng Y., Liu Q., Bao J.K., Yang J.M.: Autophagic pathwaysas new targets for cancer drug development. Acta Pharmacol. Sin.,2010; 31: 1154-1164
  Google Scholar
• 45. Lockshin R.A., Zakeri Z.: Apoptosis, autophagy, and more. Int. J.Biochem. Cell Biol., 2004; 36: 2405-2419
  Google Scholar
• 46. Mancias J.D., Kimmelman A.C.: Targeting autophagy addictionin cancer. Oncotarget, 2011; 2: 1302-1306
  Google Scholar
• 47. Martyniszyn L., Orłowski P., Krzyżowska M., Niemiałtowski M.G.:Autofagia w zakażeniach wirusowych i bakteryjnych: molekularnaruletka. Postępy Biol. Kom., 2008; 35: 351-368
  Google Scholar
• 48. Martyniszyn L., Szulc L., Boratyńska A., Niemiałtowski M.G.:Beclin 1 is involved in regulation of apoptosis and autophagy duringreplication of ectromelia virus in permissive L929 cells. Arch.Immunol. Ther. Exp., 2011; 59: 463-471
  Google Scholar
• 49. Maycotte P., Thorburn A.: Autophagy and cancer therapy. CancerBiol. Ther., 2011; 11: 127-137
  Google Scholar
• 50. Mehrpour M., Esclatine A., Beau I., Codogno P.: Autophagy inhealth and disease. 1. Regulation and significance of autophagy: anoverview. Am. J. Physiol. Cell Physiol., 2010; 298: C776-C785
  Google Scholar
• 51. Mizushima N.: Autophagy: process and function. Genes Dev.,2007; 21: 2861-2873
  Google Scholar
• 52. Mizushima N., Levine B.: Autophagy in mammalian developmentand differentiation. Nat. Cell Biol., 2010; 12: 823-830
  Google Scholar
• 53. Mizushima N., Ohsumi Y., Yoshimori T.: Autophagosome formationin mammalian cells. Cell Struct. Funct., 2002; 27: 421-429
  Google Scholar
• 54. Morselli E., Galluzzi L., Kepp O., Criollo A., Maiuri M.C., TavernarakisN., Madeo F., Kroemer G.: Autophagy mediates pharmacologicallifespan extension by spermidine and resveratrol. Aging,2009; 1: 961-970
  Google Scholar
• 55. Notte A., Leclere L., Michiels C.: Autophagy as a mediator ofchemotherapy-induced cell death in cancer. Biochem. Pharmacol.,2011; 82: 427-434
  Google Scholar
• 56. Perycz M., Świech Ł., Malik A., Jaworski J.: mTOR w fizjologiii patologii układu nerwowego. Postępy Biol. Kom., 2007; 34: 511-525
  Google Scholar
• 57. Qu X., Zou Z., Sun Q., Luby-Phelps K., Cheng P., Hogan R.N., GilpinC., Levine B.: Autophagy gene-dependent clearance of apoptotic cellsduring embryonic development. Cell, 2007; 128: 931-946
  Google Scholar
• 58. Reggiori F., Shintani T., Nair U., Klionsky D.J.: Atg9 cycles betweenmitochondria and the pre-autophagosomal structure inyeasts. Autophagy, 2005; 1: 101-109
  Google Scholar
• 59. Rikiishi H.: Autophagic action of new targeting agents in headand neck oncology. Cancer Biol. Ther., 2012; 13: 978-991
  Google Scholar
• 60. Rosenfeldt M.T., Ryan K.M.: The multiple roles of autophagy incancer. Carcinogenesis, 2011; 32: 955-963
  Google Scholar
• 61. Rosich L., Xargay-Torrent S., López-Guerra M., Campo E., ColomerD., Roué G.: Counteracting autophagy overcomes resistanceto everolimus in mantle cell lymphoma. Clin. Cancer Res., 2012;18: 5278-5289
  Google Scholar
• 62. Roy S., Debnath J.: Autophagy and tumorigenesis. Semin. Immunopathol.,2010; 32: 383-396
  Google Scholar
• 63. Rubinsztein D.C., Gestwicki J.E., Murphy L.O., Klionsky D.J.: Potentialtherapeutic applications of autophagy. Nat. Rev. Drug Discov.,2007; 6: 304-312
  Google Scholar
• 64. Schwartz-Roberts J.L., Shajahan A.N., Cook K.L., Wärri A., AbuAsabM., Clarke R.: GX15-070 (obatoclax) induces apoptosis and inhibitscathepsin D – and L-mediated autophagosomal lysis in antiestrogen-resistantbreast cancer cells. Mol. Cancer Ther., 2013; 12: 448-459
  Google Scholar
• 65. Sridharan S., Basu A.: S6 kinase 2 promotes breast cancer cellsurvival via Akt. Cancer Res., 2011; 71: 2590-2599
  Google Scholar
• 66. Subauste C.S.: Autophagy as an antimicrobial strategy. ExpertRev. Anti Infect. Ther., 2009; 7: 743-752
  Google Scholar
• 67. Sun Q., Fan W., Zhong Q.: Regulation of Beclin 1 in autophagy.Autophagy, 2009; 5: 713-716
  Google Scholar
• 68. Suzuki K., Kubota Y., Sekito T., Ohsumi Y.: Hierarchy of Atg proteinsin pre-autophagosomal structure organization. Genes Cells,2007; 12: 209-218
  Google Scholar
• 69. Tanida I., Ueno T., Kominami E.: LC3 and autophagy. MethodsMol. Biol., 2008; 445: 77-88
  Google Scholar
• 70. Tasdemir E., Chiara Maiuri M., Morselli E., Criollo A., D’Amelio M.,Djavaheri-Mergny M., Cecconi F., Tavernarakis N., Kroemer G.: A dualrole of p53 in the control of autophagy. Autophagy, 2008; 4: 810-814
  Google Scholar
• 71. Tooze S.A., Yoshimori T.: The origin of the autophagosomalmembrane. Nat. Cell Biol., 2010: 12: 831-835
  Google Scholar
• 72. Turcotte S., Giaccia A.J.: Targeting cancer cells through autophagyfor anticancer therapy. Curr. Opin. Cell Biol., 2010; 22: 246-251
  Google Scholar
• 73. Wang C., Wang Y., McNutt M.A., Zhu W.G.: Autophagy processis associated with anti-neoplastic function. Acta Biochim. Biophys.Sin., 2011; 43: 425-432
  Google Scholar
• 74. Weidberg H., Shpilka T., Shvets E., Elazar Z.: Mammalian Atg8s:one is simply not enough. Autophagy, 2010; 6: 808-809
  Google Scholar
• 75. Weidberg H., Shvets E., Elazar Z.: Biogenesis and cargo selectivityof autophagosomes. Annu. Rev. Biochem., 2011; 80: 125-156
  Google Scholar
• 76. Wu W.K., Coffelt S.B., Cho C.H., Wang X.J., Lee C.W., Chan F.K.,Yu J., Sung J.J.: The autophagic paradox in cancer therapy. Oncogene,2012; 31: 939-953
  Google Scholar
• 77. Yang Y.P., Liang Z.Q., Gu Z.L., Qin Z.H.: Molecular mechanism andregulation of autophagy. Acta Pharmacol. Sin., 2005; 26: 1421-1434
  Google Scholar
• 78. Yang Z., Klionsky D.J.: Mammalian autophagy: core molecularmachinery and signaling regulation. Curr. Opin. Cell Biol., 2010;22: 124-131
  Google Scholar
• 79. Zang Y., Thomas S.M., Chan E.T., Kirk C.J., Freilino M.L., DeLanceyH.M., Grandis J.R., Li C., Johnson D.E.: The next generation proteasomeinhibitors carfilzomib and oprozomib activate prosurvivalautophagy via induction of the unfolded protein response and ATF4.Autophagy, 2012; 8: 1873-1874
  Google Scholar
• 80. Zhu K., Dunner K.Jr., McConkey D.J.: Proteasome inhibitors activateautophagy as a cytoprotective response in human prostatecancer cells. Oncogene, 2010; 29: 451-462
  Google Scholar
• 81. Zhu X., Wu L., Qiao H., Han T., Chen S., Liu X., Jiang R., Wei Y.,Feng D., Zhang Y., Ma Y., Zhang S., Zhang J.: Autophagy stimulatesapoptosis in HER2-overexpressing breast cancers treated by lapatinib.J. Cell. Biochem., 2013; 114: 2643-2653
  Google Scholar

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