AUTOPHAGY AND RENAL CELL CARCINOMA: WHAT DO WE KNOW SO FAR?
Keywords:
renal cell carcinoma, autophagy, mTOR complex
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney tumor in adults, accounting for approximately 90% of kidney malignances and it occurs usually between ages of 60 and 70 years. The 5-year overall survival rate for all RCC types is 49%. Since RCCs are resistant to many different radio and chemotherapeutics that act via apoptosis induction, the development of new approaches to RCC treatment is still in the focus of modern urology. In particular, in recent years, autophagy in RCC has been widely studied as a mechanism of cell extinction through which tumor cells can overcome resistance to apoptosis activation therapy. Autophagy is often referred to as a double-edged sword because it can be a process that allows cells of cancer to survive and, on the other hand and under other conditions, it can be a cell dying mechanism, independent or closely related to other cell death modalities, like apoptosis and necrosis. The central role in the tempering of the process of autophagy, in general, belongs to the mTOR complex (mammalian target of rapamycin), which integrates numerous signals that affect autophagy, such as growth factors, nutrients, various stressors and the energy status of the cell. In RCC, the most important is PI3K/AKT/mTOR signaling pathway since activation of this signaling leads to survival of tumor cells through mTOR activation and thus autophagy inhibition. Up to now, it was found that autophagy markers such as Beclin-1 and LC3-II can be considered as prognostic markers for RCC since the high level of Beclin 1 was detected in tissues and cells of RCC (A498 and ACHN cell lines) and that tumor cell mobility is promoted by the up-regulated expression of LC3.
Therefore, a progress in RCC therapy can be expected from the development and synthesis of specific compounds targeting autophagy as well as the therapy based on their combination.
References
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48. Tsang C., Qi H., Liu L., Zheng X. Targeting mammaliam target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007; 12:112 – 24.
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51. Anbalagan, S., Pires, I. M., Blick, C., Hill, M. A., Ferguson, D. J., Chan, D. A., et al. (2012). Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy. Radiother. Oncol. 103 (3), 388–393.
52. Cao P, Jiang XJ, Xi ZJ. Sunitinib induces autophagy via suppressing Akt/mTOR pathway in renal cell carcinoma. Beijing Da Xue Xue Bao Yi Xue Ban. 2016,48(1): 584-589.
53. Zheng B, Mao JH, Qian L, et al. Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma. CANCER LETT. 2015,357(2): 468-475.
54. Li F, Ma Z, Guan Z, et al. Autophagy induction by silibinin positively contributes to its anti-metastatic capacity via AMPK/mTOR pathway in renal cell carcinoma. INT J MOL SCI. 2015,16(4): 8415-8429
55. Liu, S., Xie, F., Wang, H., Liu, Z., Liu, X., Sun, L., et al. (2015c). Ubenimex inhibits cell proliferation, migration and invasion in renal cell carcinoma: the effect is autophagy-associated. Oncol. Rep. 33 (3), 1372–1380.
56. Ying-hua He and Guo Tian. Autophagyas a Vital Therapy Target for Renal Cell Carcinoma. Pharacology.2021; 11:518225
57. Lotze MT, Maranchie J, Appleman L. Inhibiting autophagy: A novel approach for the treatment of renal cell carcinoma. CANCER J. 2013,19(4): 341-347.
58. Trace M. Jones, Jennifer S. Carew and Stefan T. Nawrocki. Therapeutic Targeting of Autophagy for Renal Cell Carcinoma Therapy. Cancers 2020, 12, 1185
59. Haas, N.B.; Appleman, L.J.; Stein, M.; Redlinger, M.; Wilks, M.; Xu, X.; Onorati, A.; Kalavacharla, A.; Kim, T.; Zhen, C.J.; et al. Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clin. Cancer Res. 2019, 25, 2080–2087.;
60. Mahalingam, D.; Mita, M.; Sarantopoulos, J.; Wood, L.; Amaravadi, R.K.; Davis, L.E.; Mita, A.C.; Curiel, T.J.; Espitia, C.M.; Nawrocki, S.T.; et al. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014, 10, 1403–1414.
2. Ridge CA, Pua BB, Madoff DC. Epidemiology and staging of renal cell carcinoma. Seminars in interventional radiology. 2014;31(1):3-8.
3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. European journal of cancer (Oxford, England : 1990). 2013;49(6):1374-403.
4. Bergstrom A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer--a quantitative review. British journal of cancer. 2001;85(7):984-90.
5. Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, et al. The epidemiology of renal cell carcinoma. European urology. 2011;60(4):615-21.
6. Grant Stewart D, O'Mahony FC, Powles T, Riddick AC, Harrison DJ, Faratian D. What can molecular pathology contribute to the management of renal cell carcinoma? Nature reviews Urology. 2011;8(5):255-65.
7. Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Annals of oncology : official journal of the European Society for Medical Oncology. 2019;30(5):706-20.
8. A Phase 3, Randomized, Open-Label Study of Nivolumab Combined With Ipilimumab Versus Sunitinib Monotherapy in Subjects With Previously Untreated, Advanced or Metastatic Renal Cell Carcinoma. 2015 p. NCT02231749.
9. Sim, S.H., et al. Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma. Br J Cancer, 2012. 107: 1131.
10. Sabatino, M., et al. Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol, 2009. 27: 2645.
11. Li, G., et al. Serum carbonic anhydrase 9 level is associated with postoperative recurrence of conventional renal cell cancer. J Urol, 2008.
12. Choueiri, T.K., et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol, 2014. 25: 1603.
13. Choueiri, T.K., et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015. 373: 1814.
14. Motzer, R.J., et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015. 373: 1803.
15. Yongchang Lai, Tao Zeng, Xiongfa Liang, Weizou Wu, Fangling Zhong and Wenqi Wu. Cell death-related molecules and biomarkers for renal cell carcinoma targeted therapy. Cancer Cell Int. (2019) 19:221
16. Kim Y, Kim YS, Kim DE, Lee JS, Song JH, Kim HG, et al. BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy. (2013) 9:2126– 39.
17. Mizushima N, Levine B, Cuervo AM, Klionsky DJ 2008. Autophagy fights disease through cellular self-digestion. Nature 451: 1069–1075
18. Xie Z, Klionsky DJ 2007. Autophagosome formation: Core machinery and adaptations. Nat Cell Biol 9: 1102–1109
19. Rosenfeldt MT, Ryan KM 2009. The role of autophagy in tumour development and cancer therapy. Expert Rev Mol Med 11: e36
20. Rosenfeldt MT, Ryan KM 2011. The multiple roles of autophagy in cancer. Carcinogenesis 32: 955–963
21. Mehrpour M, Esclatine A, Beau I, Codogno P 2010. Overview of macroautophagy regulation in mammalian cells. Cell Res 20: 748–762
22. Ding W., Ni H., Gao W., et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 2007; 282:4702 – 10
23. Reef S., Zalckvar E., Shifman O., et al. A short mitochondrial form of p10ARF induces autophagy and caspase-independent cell death. Mol Cell 2006; 22:463 – 75
24. Scherz-Shouval R., Snvets E., Fass E., Shorer H., Gil L., Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2007; 26:1749 – 60.
25. Cao Q, Bai P. Role of Autophagy in Renal Cancer. Journal of Cancer. 2019;10(11):2501-9
26. LoPiccolo J, Blumenthal GM, Bernstein WB, et al. Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations. Drug Resist Updat. 2008,11(1-2): 32-50
27. Huifang Guo, Peter German, Shanshan Bai, Sean Barnes, Wei Guo, Xiangjie Qi, Hongxiang Lou, Jiyong Liang, Eric Jonasch, Gordon B. Mills, and Zhiyong Ding1. The PI3K/AKT Pathway and Renal Cell Carcinoma. J Genet Genomics. 2015; 42(7): 343–353
28. Milan Radovanovic, Sasenka Vidicevic, Jelena Tasic, Nina Tomonjic, Zeljka Stanojevic, Predrag Nikic, Aleksandar Vuksanovic, Zoran Dzamic, Uros Bumbasirevic, Aleksandra Isakovic, Vladimir Trajkovic. Role of AMPK/mTOR-independent autophagy in clear cell renal cell carcinoma. J Investig Med 2020;0:1–8.
29. Creighton, C.J.; Morgan, M.; Gunaratne, P.H.; Wheeler, D.A.; Gibbs, R.A.; Robertson, G.; Chu, A.; Beroukhim, R.; Cibulskis, K.; Signoretti, S.; et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013, 499, 43–49;
30. Duran, I.; Lambea, J.; Maroto, P.; González-Larriba, J.L.; Flores, L.; Granados-Principal, S.; Graupera, M.; Sáez, B.; Vivancos, A.; Casanovas, O. Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action. Target. Oncol. 2017, 12, 19–35.
31. Demin Fan, Qiang Liu, Fei Wu, Na Liu, Hongyi Qu, Yijiao Yuan, Yong Li, Huayu Gao, Juntao Ge, Yue Xu, Hao Wang, Qingyong Liu and Zuohui Zhao. Prognostic significance of PI3K/AKT/ mTOR signaling pathway members in clear cell renal cell carcinoma. (2020), PeerJ. DOI 10.7717/peerj.9261
32. Seo SU, Woo SM, Lee HS, et al. MTORC1/2 inhibitor and curcumin induce apoptosis through lysosomal membrane permeabilization-mediated autophagy. ONCOGENE. 2018,37(38): 5205-5220
33. Arico S, Petiot A, Bauvy C, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J BIOL CHEM. 2001,276(38): 35243-35246
34. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annual review of pathology. 2009;4:127-50.
35. Shin Lee J, Seok Kim H, Bok Kim Y, Cheol Lee M, Soo Park C. Expression of PTEN in renal cell carcinoma and its relation to tumor behavior and growth. Journal of surgical oncology. 2003;84(3):166-72.
36. Brenner W, Farber G, Herget T, Lehr HA, Hengstler JG, Thuroff JW. Loss of tumor suppressor protein PTEN during renal carcinogenesis. International journal of cancer. 2002;99(1):53-7.
37. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene. 2008;27(41):5477-85.
38. Feng Z, Hu W, de Stanchina E, et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: Stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. CANCER RES. 2007,67(7): 3043-3053.
39. Haitel A, Wiener HG, Baethge U, et al. Mdm2 expression as a prognostic indicator in clear cell renal cell carcinoma: Comparison with p53 overexpression and clinicopathological parameters. CLIN CANCER RES. 2000,6(5): 1840-1844;
40. Zigeuner R, Ratschek M, Rehak P, et al. Value of p53 as a prognostic marker in histologic subtypes of renal cell carcinoma: A systematic analysis of primary and metastatic tumor tissue. UROLOGY. 2004,63(4): 651-655
41. Warburton HE, Brady M, Vlatkovic N, et al. P53 regulation and function in renal cell carcinoma. CANCER RES. 2005,65(15): 6498-6503
42. Noon AP, Vlatkovic N, Polanski R, Maguire M, Shawki H, Parsons K, et al. p53 and MDM2 in renal cell carcinoma: biomarkers for disease progression and future therapeutic targets? Cancer. 2010;116(4):780-90.
43. Guo, Y., Zhang, H. C., Xue, S., and Zheng, J. H. (2019). Receptors for advanced glycation end products is associated with autophagy in the clear cell renal cell carcinoma. J. Canc. Res. Therapeut. 15 (2), 317–323.
44. Gossage, L., and Eisen, T. (2010). Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nat. Rev. Clin. Oncol. 7 (5), 277–288
45. Mikhaylova, O., Stratton, Y., Hall, D., Kellner, E., Ehmer, B., Drew, A. F., et al. (2012). VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Canc. Cell. 21 (4), 532–546
46. Bursch W., Ellinger A., Kienzl H., et al. Active cell death induced by the anti-estrogens tamoxifen and ICI164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 1996; 17:1595 – 607
47. Qian W., Liu J., Jin J., Ni W., Xu W. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via upregulation of Beclin-1. Leuk Res 2007; 31:329 – 39.
48. Tsang C., Qi H., Liu L., Zheng X. Targeting mammaliam target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007; 12:112 – 24.
49. Katayama M., Kawaguchi T., Berger M., Pieper R. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ 2007; 14:548 – 58.
50. Turcotte, S., Chan, D. A., Sutphin, P. D., Hay, M. P., Denny, W. A., and Giaccia, A. J. (2008). A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Canc. Cell. 14 (1), 90–102
51. Anbalagan, S., Pires, I. M., Blick, C., Hill, M. A., Ferguson, D. J., Chan, D. A., et al. (2012). Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy. Radiother. Oncol. 103 (3), 388–393.
52. Cao P, Jiang XJ, Xi ZJ. Sunitinib induces autophagy via suppressing Akt/mTOR pathway in renal cell carcinoma. Beijing Da Xue Xue Bao Yi Xue Ban. 2016,48(1): 584-589.
53. Zheng B, Mao JH, Qian L, et al. Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma. CANCER LETT. 2015,357(2): 468-475.
54. Li F, Ma Z, Guan Z, et al. Autophagy induction by silibinin positively contributes to its anti-metastatic capacity via AMPK/mTOR pathway in renal cell carcinoma. INT J MOL SCI. 2015,16(4): 8415-8429
55. Liu, S., Xie, F., Wang, H., Liu, Z., Liu, X., Sun, L., et al. (2015c). Ubenimex inhibits cell proliferation, migration and invasion in renal cell carcinoma: the effect is autophagy-associated. Oncol. Rep. 33 (3), 1372–1380.
56. Ying-hua He and Guo Tian. Autophagyas a Vital Therapy Target for Renal Cell Carcinoma. Pharacology.2021; 11:518225
57. Lotze MT, Maranchie J, Appleman L. Inhibiting autophagy: A novel approach for the treatment of renal cell carcinoma. CANCER J. 2013,19(4): 341-347.
58. Trace M. Jones, Jennifer S. Carew and Stefan T. Nawrocki. Therapeutic Targeting of Autophagy for Renal Cell Carcinoma Therapy. Cancers 2020, 12, 1185
59. Haas, N.B.; Appleman, L.J.; Stein, M.; Redlinger, M.; Wilks, M.; Xu, X.; Onorati, A.; Kalavacharla, A.; Kim, T.; Zhen, C.J.; et al. Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clin. Cancer Res. 2019, 25, 2080–2087.;
60. Mahalingam, D.; Mita, M.; Sarantopoulos, J.; Wood, L.; Amaravadi, R.K.; Davis, L.E.; Mita, A.C.; Curiel, T.J.; Espitia, C.M.; Nawrocki, S.T.; et al. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014, 10, 1403–1414.