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Цитология, 2023, T. 65, № 3, стр. 246-258

Роль интегрированного ответа опухолевых клеток на стресс, аутофагии и шаперонов в возникновении рецидивов резистентных опухолей

С. Г. Зубова 1, *, О. О. Гнедина 1

1 Институт цитологии РАН
Санкт-Петербург, Россия

* E-mail: egretta_julia@mail.ru

Поступила в редакцию 07.11.2022
После доработки 27.01.2023
Принята к публикации 01.02.2023

Аннотация

Химио- и радиотерапия представляют собой для опухолевых клеток колоссальный стрессорный фактор. В ответ на терапию активируется вся эволюционно закрепленная реакция клеток на стресс. Это происходит на всех уровнях организации клетки, а именно на белковом уровне и уровне ДНК. В этот ответ включаются система протеостаза клетки, системы репарации ДНК, гены-онкосупрессоры и многие другие системы клетки. Мы рассмотрим роль в этих процессах основных систем протеостаза, а именно макроаутофагии и шаперонов, которые являются частью интегрированного ответа клетки на стресс. В результате ответа клетки на стресс, опухолевая клетка становится еще менее дифференцированной, активируя необходимые для выживания гены и внутриклеточные системы. Клетки, которые ответили на стресс таким образом, имеют более агрессивный фенотип, который оказывается значительно устойчивее к терапии. Под воздействием стресса клетка эволюционно упрощается, что дает ей дополнительные шансы для выживания. Аутофагия, с одной стороны, способствует снижению дифференцировки опухолевой клетки, ее пластичности, а с другой – поддерживает определенную стабильность, отвечая за целостность генома и освобождая клетку от поврежденных органелл и дефектных белков. И аутофагия, и шапероны способствуют приобретению опухолью множественной лекарственной устойчивости, что еще более затрудняет терапию. Понимание этих процессов с учетом многостадийности канцерогенеза делает возможной разработку новых терапевтических подходов.

Ключевые слова: аутофагия, шапероны, ДНК стабильность, МЛУ фенотип, старение, апоптоз, стволовой компонент

Список литературы

  1. Aggarwal S., Tsuruo T., Gupta S.J. 1997. Altered expression and function of P-glycoprotein (170 kDa), encoded by the MDR 1 gene, in T cell subsets from aging humans. Clin. Immunol. V. 17. P. 448. https://doi.org/10.1023/a:1027363525408

  2. Albakova Z., Armeev G.A., Kanevski L.M., Kovalenko E.I., Sapozhnikov A.M. 2020. HSP70 multi-functionality in cancer. Cells. V. 9. P. 587. https://doi.org/10.3390/cells9030587

  3. Anand S.K., Sharma A., Singh N., Kakkar P. 2020. Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity. DNA Repair (Amst). V. 86. P. 102 748. https://doi.org/10.1016/j.dnarep.2019.102748

  4. Apel A., Herr I., Schwarz H., Rodemann P., Mayer A. 2008. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. V. 68. P. 1485. https://doi.org/10.1158/0008-5472.CAN-07-0562

  5. Benassi B., Fanciulli M., Fiorentino F., Porrello A., Chiorino G., Loda M., Zupi G., Biroccio A. 2006. c-Myc phosphorylation is required for cellular response to oxidative stress. Mol. Cell. V. 21. P. 509. https://doi.org/10.1016/j.molcel.2006.01.009

  6. Bradley E., Bieberich E., Mivechi N.F., Tangpisuthipongsa D., Wang G. 2012. Regulation of embryonic stem cell pluripotency by heat shock protein 90. Stem Cells. V. 30. P. 1624. https://doi.org/10.1002/stem.1143

  7. Büchler P., Reber H.A., Lavey R.S., Tomlinson J., Büchler M.W., Friess H., Hines O.J. 2004. Tumor hypoxia correlates with metastatic tumor growth of pancreatic cancer in an orthotopic murine model. J. Surg. Res. V. 120. P. 295. https://doi.org/10.1016/j.jss.2004.02.014

  8. Chakraborty C., Agoramoorthy G. 2012. Stem cells in the light of evolution. Indian J. Med. Res. V. 135. P. 813.

  9. Chao T., Shih H.T., Hsu S.C., Chen P.J., Fan Y.S., Jeng Y.M., Shen Z.Q., Tsai T.F., Chang Z.F. 2021. Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability. Autophagy. V. 17. P. 3444. https://doi.org/10.1080/15548627.2021.1874209

  10. Chen N., Karantza-Wadsworth V. 2009. Role and regulation of autophagy in cancer. Biochim. Biophys. Acta. V. 1793. P. 1516. https://doi.org/10.1016/j.bbamcr.2008.12.013

  11. Condon K.J., Sabatini D.M. 2019. Nutrient regulation of mTORC1 at a glance. J. Cell Sci. V. 132. P. jcs222570. https://doi.org/10.1242/jcs.222570

  12. Das C.K., Mandal M., Kögel D. 2018a. Pro-survival autophagy and cancer cell resistance to therapy. Cancer Metastasis Rev. V. 37. P. 749. https://doi.org/10.1007/s10555-018-9727-z

  13. Das C.K., Linder B., Bonn F., Rothweiler F., Dikic I., Michaelis M., Cinatl J., Mandal M., Kögel D. 2018b. BAG3 overexpression and cytoprotective autophagy mediate apoptosis resistance in chemoresistant breast cancer cells. Neoplasia. V. 20. P. 263. https://doi.org/10.1016/j.neo.2018.01.001

  14. Dinić J., Podolski-Renić A., Jovanović M., Musso L., Tsakovska I., Pajeva I., Dallavalle S., Pešić M. 2019. Novel heat shock protein 90 inhibitors suppress P-Glycoprotein activity and overcome multidrug resistance in cancer cells. Int. J. Mol. Sci. V. 20. P. 4575. https://doi.org/10.3390/ijms20184575

  15. Dubrez L., Causse S., Bonan N.B., Dumétier B., Garrido C. 2020. Heat-shock proteins: chaperoning DNA repair. Oncogene. V. 39. P. 516. https://doi.org/10.1038/s41388-019-1016-y

  16. Erenpreisa J., Salmina K., Anatskaya O., Cragg M.S. 2022. Paradoxes of cancer: survival at the brink. Semin. Cancer Biol. V. 81. P. 119. https://doi.org/10.1016/j.semcancer.2020.12.009

  17. Feng Y., Klionsky D.J. 2017. Autophagy regulates DNA repair through SQSTM1/p62. Autophagy. V. 13. P. 995. https://doi.org/10.1080/15548627.2017.1317427

  18. Galati S., Boni C., Gerra M.C., Lazzaretti M., Buschini A. 2019. Autophagy: a player in response to oxidative stress and DNA damage. Oxid. Med. Cell Longev. V. 2019. P. 5692958. https://doi.org/10.1155/2019/5692958

  19. Gomes L.R., Menck C.F.M., Leandro G.S. 2017. Autophagy roles in the modulation of DNA repair pathways. Int. J. Mol. Sci. V. 18. P. 2351 https://doi.org/10.3390/ijms18112351

  20. Gremke N., Polo P., Dort A., Schneikert J., Elmshäuser S., Brehm C., Klingmüller U., Schmitt A., Reinhardt H.C., Timofeev O., Wanzel M., Stiewe T. 2020. mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability. Nat. Commun. V. 11. P. 4684. https://doi.org/10.1038/s41467-020-18504-7

  21. Hewitt G., Korolchuk V.I. 2017. Repair, reuse, recycle: The expanding role of autophagy in genome maintenance. Trends Cell Biol. V. 27. P. 340. https://doi.org/10.1016/j.tcb.2016.11.011

  22. Ikwegbue P.C., Masamba P., Mbatha L.S., Oyinloye B.E., Kappo A.P. 2019. Interplay between heat shock proteins, inflammation and cancer: a potential cancer therapeutic target. Am. J. Cancer Res. V. 9. P. 242.

  23. Jewer M., Lee L., Leibovitch M., Zhang G., Liu J., Findlay S.D., Vincent K.M., Tandoc K., Dieters-Castator D., Quail D.F., Dutta I., Coatham M., Xu Z., Puri A., Guan B.J. et al. 2020. Translational control of breast cancer plasticity. Nat. Commun. V. 11. P. 2498. https://doi.org/10.1038/s41467-020-16352-z

  24. Juretschke T., Beli P. 2021. Causes and consequences of DNA damage-induced autophagy. Matrix Biol. V. 100–101. P. 39. https://doi.org/10.1016/j.matbio.2021.02.004

  25. Kametaka S., Okano T., Ohsumi M., Ohsumi Y. 1998. Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. J. Biol. Chem. V. 273. P. 22284. https://doi.org/10.1074/jbc.273.35.22284

  26. Karabicici M., Alptekin S., Fırtına Karagonlar Z., Erdal E. 2021. Doxorubicin-induced senescence promotes stemness and tumorigenicity in EpCAM-/CD133- nonstem cell population in hepatocellular carcinoma cell line, HuH-7. Mol. Oncol. V. 15. P. 2185. https://doi.org/10.1002/1878-0261.12916

  27. Kim H.B., Lee S.H., Um J.H., Oh W.K., Kim D.W., Kang C.D., Kim S.H. 2015a. Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1. Oncotarget. V. 6. P. 36202. https://doi.org/10.18632/oncotarget.5343

  28. Kim B.M., Hong Y., Lee S., Liu P., Lim J.H., Lee Y.H., Lee T.H., Chang K.T., Hong Y. 2015б. Therapeutic implications for overcoming radiation resistance in cancer therapy. Int. J. Mol. Sci. V. 16. P. 26880. https://doi.org/10.3390/ijms161125991

  29. Kögel D., Linder B., Brunschweiger A., Chines S., Behl C. 2020. At the crossroads of apoptosis and autophagy: multiple roles of the co-chaperone BAG3 in stress and therapy resistance of cancer. Cells. V. 9. P. 574. https://doi.org/10.3390/cells9030574

  30. Kumar S., Stokes J. 3rd, Singh U.P., Scissum Gunn K., Acharya A., Manne U., Mishra M. 2016. Targeting Hsp70: A possible therapy for cancer. Cancer Lett. V. 374. P. 156. https://doi.org/10.1016/j.canlet.2016.01.056

  31. Li Y.J., Lei Y.H., Yao N., Wang C.R., Hu N., Ye W.C., Zhang D.M., Chen Z.S., Chin J. 2017. Autophagy and multidrug resistance in cancer. Cancer. V. 36. P. 52. https://doi.org/10.1186/s40880-017-0219-2

  32. Liang B., Liu X., Liu Y., Kong D., Liu X., Zhong R., Ma S. 2016. Inhibition of autophagy sensitizes MDR-phenotype ovarian cancer SKVCR cells to chemotherapy. Biomed. Pharmacother. V. 82. P. 98. https://doi.org/10.1016/j.biopha.2016.04.054

  33. Lin F., Gao L., Su Z., Cao X., Zhan Y., Li Y., Zhang B. 2018. Knockdown of KPNA2 inhibits autophagy in oral squamous cell carcinoma cell lines by blocking p53 nuclear translocation. Oncol. Rep. V. 40. P. 179. https://doi.org/10.3892/or.2018.6451

  34. Liu J., Chang B., Li Q., Xu L., Liu X., Wang G., Wang Z., Wang L. 2019. Redox-responsive dual drug delivery nanosystem suppresses cancer repopulation by abrogating doxorubicin-promoted cancer stemness, metastasis, and drug resistance. Adv. Sci. (Weinh). V. 6. P. 1801987. https://doi.org/10.1002/advs.201801987

  35. Margulis B., Tsimokha A., Zubova S., Guzhova I. 2020. Molecular chaperones and proteolytic machineries regulate protein homeostasis in aging cells. Cells. V. 9. P. 1308. https://doi.org/10.3390/cells9051308

  36. Mehta A.P., Supekova L., Chen J.H., Petonjamasp K., Webster P., Ko Y., Henderson S.C., McDermott G., Supek F., Schullz P.G. 2018. Engineering yeast endosymbionts as a step toward the evolution of mitochondria. Proc. Natl. Acad. Sci. USA. V. 115. P. 11796–11801. https://doi.org/10.1073/pnas.1813143115

  37. Mendez F., Sandigursky M., Franklin W.A., Kenny M.K., Kureekattil R., Bases R. 2000. Heat-shock proteins associated with base excision repair enzymes in HeLa cells. Radiat Res. 153:186–195. https://doi.org/10.1667/0033-7587(2000)153[0186:hspawb]-2.0.co;2

  38. Menendez J.A., Vellon L., Oliveras-Ferraros C., Cufí S., Vazquez-Martin A. 2011. mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle. V. 10. P. 3658. https://doi.org/10.4161/cc.10.21.18128

  39. Mizushima N. 2007. Autophagy: process and function. Genes Dev. V. 21. P. 2861. https://doi.org/10.1101/gad.1599207

  40. Ozates N.P., Soğutlu F., Lerminoglu F., Demir B., Gunduz C., Shademan B. 2021. Effects of rapamycin and AZD3463 combination on apoptosis, autophagy, and cell cycle for resistance control in breast cancer. Life Sci. V. 264. P. 118643. https://doi.org/10.1016/j.lfs.2020.118643

  41. Pan Y., Gao Y., Chen L, Gao G., Dong H., Yang Y., Dong B., Chen X. 2011. Targeting autophagy augments in vitro and in vivo antimyeloma activity of DNA-damaging chemotherapy. Clin. Cancer Res. V. 17. P. 3248. https://doi.org/10.1158/1078-0432.CCR-10-0890

  42. Pandita T.K., Higashikubo R., Hunt C.R. 2004. HSP70 and genomic stability. Cell Cycle. V. 3. P. 591. https://doi.org/10.4161/cc.3.5.863

  43. Pani G., Galeotti T., Chiarugi P. 2010. Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev. V. 29. P. 351. https://doi.org/10.1007/s10555-010-9225-4

  44. Pennisi R., Ascenzi P., di Masi A. 2015. Hsp90: a new player in DNA repair? Biomolecules. V. 5. P. 2589. https://doi.org/10.3390/biom5042589

  45. Quanz M., Herbette A., Sayarath M., Koning L., Dubois T., Sun J.S., Dutreix M. 2012. Heat shock protein 90α (Hsp90α) is phosphorylated in response to DNA damage and accumulates in repair foci. J. Biol. Chem. V. 287. P. 8803. https://doi.org/10.1074/jbc.M111.320887

  46. Roshani-Asl E., Mansori B., Mohammadi A., Najafi S., Danesh-Pouya F., Rasmi Y. 2020. Interaction between DNA damage response and autophagy in colorectal cancer. Gene. V. 730. P. 144 323. https://doi.org/10.1016/j.gene.2019.144323

  47. Roufayel R., Kadry S. 2019. Molecular chaperone HSP70 and key regulators of apoptosis – A review. Curr. Mol. Med. V. 19. P. 315. https://doi.org/10.2174/1566524019666190326114720

  48. Sannino S., Yates M.E., Schurdak M.E., Oesterreich S., Lee A.V., Wipf P., Brodsky J.L. 2021. Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised. Elife. V. 10. P. e64977. https://doi.org/10.7554/eLife.64977

  49. Smith A.G., Macleod K.F. 2019. Autophagy, cancer stem cells and drug resistance. J. Pathol. V. 7. P. 708. https://doi.org/10.1002/path.5222

  50. Song X., Lee D.H., Dilly A.K., Lee Y.S., Choudry H.A., Kwon Y.T., Bartlett D.L., Lee Y.J. 2018. Crosstalk between apoptosis and autophagy is regulated by the arginylated BiP/Beclin-1/p62 complex. Mol. Cancer Res. V. 16. P. 1077. https://doi.org/10.1158/1541-7786.MCR-17-0685

  51. Sottile M.L., Nadin S.B. 2018. Heat shock proteins and DNA repair mechanisms: an updated overview. Cell Stress Chaperones. V. 23. P. 303. https://doi.org/10.1007/s12192-017-0843-4

  52. Stagni V., Ferri A., Cirotti C., Barilà D. 2021. ATM kinase-dependent regulation of autophagy: a key player in senescence? Front. Cell Dev. Biol. V. 8. P. 599048. https://doi.org/10.3389/fcell.2020.599048

  53. Sun W.L., Lan D., Gan T.Q., Cai Z.W. 2015. Autophagy facilitates multidrug resistance development through inhibition of apoptosis in breast cancer cells. Neoplasma. V. 62. P. 199. https://doi.org/10.4149/neo_2015_025

  54. Tabata M., Tsubaki M., Takeda T., Tateishi K., Maekawa S., Tsurushima K., Imano M., Satou T., Ishizaka T., Nishida S. 2020. Inhibition of HSP90 overcomes melphalan resistance through downregulation of Src in multiple myeloma cells. Clin. Exp. Med. V. 20. P. 63. https://doi.org/10.1007/s10238-019-00587-2

  55. Tian X., Zhang S., Zhou L., Seyhan A.A., Hernandez Borrero L., Zhang Y., El-Deiry W.S. 2021. Targeting the integrated stress response in cancer therapy. Front. Pharmacol. V. 12. P. 747837. https://doi.org/10.3389/fphar.2021.747837

  56. Tian Z.C., Wang J.Q., Ge H.J. 2019. Apatinib ameliorates doxorubicin-induced migration and cancer stemness of osteosarcoma cells by inhibiting Sox2 via STAT3 signalling. Orthop. Translat. V. 22. P. 132. https://doi.org/10.1016/j.jot.2019.07.003

  57. Trigos A.S, Pearson R.B, Papenfuss A.T, Goode D.L. 2017. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proc. Natl. Acad. Sci. USA. V. 114. P. 6406.

  58. Vilaboa N.E., Galán A., Troyano A., de Blas E., Aller P. 2000. Regulation of multidrug resistance 1 (MDR1)/P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). J. Biol. Chem. V. 275. P. 24970. https://doi.org/10.1074/jbc.M909136199

  59. Vilas-Boas V., Silva R., Gaio A.R., Martins A.M., Lima S.C., Cordeiro-da-Silva A., Bastos M.L., Remião F. 2011. P-glycoprotein activity in human Caucasian male lymphocytes does not follow its increased expression during aging. Cytometry A. V. 79. P. 912. https://doi.org/10.1002/cyto.a.21135

  60. Wang R., Shao F., Liu Z., Zhang J., Wang S., Liu J., Liu H., Chen H., Liu K., Xia M., Wang Y. 2013. The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-κB and disruption of mitochondria-dependent pathways. Chem. Biol. Interact. V. 205. P. 1. https://doi.org/10.1016/j.cbi.2013.06.007

  61. Wang Y., Zhang N., Zhang L., Li R., Fu W., Ma K., Li X., Wang L., Wang J., Zhang H., Gu W., Zhu W.G., Zhao Y. 2016. Autophagy regulates chromatin ubiquitination in DNA damage response through elimination of SQSTM1/p62. Mol. Cell. V. 63. P. 34. https://doi.org/10.1016/j.molcel.2016.05.027

  62. Wang F., Xia X., Yang C., Shen J., Mai J., Kim H.C., Kirui D., Kang Y., Fleming J.B., Koay E.J., Mitra S., Ferrari M., Shen H. 2018. SMAD4 Gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy. Clin. Cancer Res. V. 24. P. 3176. https://doi.org/10.1158/1078-0432.CCR-17-3435

  63. Wawrzynow B., Zylicz A., Zylicz M. 2018. Chaperoning the guardian of the genome. The two-faced role of molecular chaperones in p53 tumor suppressor action. Biochim. Biophys. Acta Rev. Cancer. V. 1869. P. 161. https://doi.org/10.1016/j.bbcan.2017.12.004

  64. Yang S., Wang X., Contino G., Liesa M, Sahin E., Ying H., Bause A., Li Y., Stommel J.M., Dell’antonio G., Mautner J., Tonon G., Haigis M., Shirihai O.S., Doglioni C. et al. 2011. Pancreatic cancers require autophagy for tumor growth. Genes Dev. V. 25. P. 717. https://doi.org/10.1101/gad.2016111

  65. Zhang D., Tang B., Xie X., Xiao Y.F., Yang S.M., Zhang J.W. 2015. The interplay between DNA repair and autophagy in cancer therapy. Cancer Biol. Ther. V. 16. P. 1005. https://doi.org/10.1080/15384047.2015.1046022

  66. Zhang H., Chen J., Zeng Z., Que W., Zhou L. 2013. Knockdown of DEPTOR induces apoptosis, increases chemosensitivity to doxorubicin and suppresses autophagy in RPMI-8226 human multiple myeloma cells in vitro. Int. J. Mol. Med. V. 31. P. 1127. https://doi.org/10.3892/ijmm.2013.1299

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