PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review)

Miricescu,Daniela; Balan,Daniela Gabriela; Tulin,Adrian; Stiru,Ovidiu; Vacaroiu,Ileana Adela; Mihai,Doina Andrada; Popa,Cristian Constantin; Papacocea,Raluca Ioana; Enyedi,Mihaly; Sorin,Nedelea Andrei; Vatachki,Guenadiy; Georgescu,Dragoș Eugen; Nica,Adriana Elena; Stefani,Constantin

doi:10.3892/etm.2021.9972

PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review)

Authors:
- Daniela Miricescu
- Daniela Gabriela Balan
- Adrian Tulin
- Ovidiu Stiru
- Ileana Adela Vacaroiu
- Doina Andrada Mihai
- Cristian Constantin Popa
- Raluca Ioana Papacocea
- Mihaly Enyedi
- Nedelea Andrei Sorin
- Guenadiy Vatachki
- Dragoș Eugen Georgescu
- Adriana Elena Nica
- Constantin Stefani
View Affiliations

Affiliations: Department of Biochemistry, Faculty of Dental Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Discipline of Physiology, Faculty of Dental Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Department of Anatomy, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Department of Cardiovascular Surgery, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Department of Nephrology and Dialysis, ‘Sf. Ioan’ Emergency Clinical Hospital, 042122 Bucharest, Romania, Discipline of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Department of Surgery, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Discipline of Physiology, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Division of Urology, ‘Prof. Dr. Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania, Department of General Surgery, ‘Fundeni’ Clinical Institute 022328 Bucharest, Romania, Department of Orthopedics, Anesthesia Intensive Care Unit, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Department of Family Medicine and Clinical Base, Dr. Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania
Published online on: March 23, 2021 https://doi.org/10.3892/etm.2021.9972
Article Number: 540
Copyright: © Miricescu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Renal cell carcinoma (RCC) accounts for over 90% of all renal malignancies, and mainly affects the male population. Obesity and smoking are involved in the pathogenesis of several systemic cancers including RCC. The phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway regulates cell growth, differentiation, migration, survival, angiogenesis, and metabolism. Growth factors, hormones, cytokine and many extracellular cues activate PI3K/AKT/mTOR. Dysregulation of this molecular pathway is frequently reported in human cancers including RCC and is associated with aggressive development and poor survival rate. mTOR is the master regulator of cell metabolism and growth, and is activated in many pathological processes such as tumour formation, insulin resistance and angiogenesis. mTOR inhibitors are used at present as drug therapy for RCC to inhibit cell proliferation, growth, survival, and the cell cycle. Temsirolimus and everolimus are two mTOR inhibitors that are currently used for the treatment of RCC. Drugs targeting the PI3K/AKT/mTOR signalling pathway may be one of the best therapeutic options for RCC.

View Figures

View References

1	Znaor A, Lortet-Tieulent J, Laversanne MA, Jemal A and Bray F: International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol. 67:519–530. 2015.PubMed/NCBI View Article : Google Scholar
2	Saad AM, Gad MM, Al-Husseini MJ, Ruhban IA, Sonbol MB and Ho TH: Trends in renal-cell carcinoma incidence and mortality in the United States in the last 2 decades: A SEER-based study. Clin Genitourin Cancer. 17:46–57.e5. 2019.PubMed/NCBI View Article : Google Scholar
3	Poprach A, Bortlíček Z, Büchler T, Melichar B, Lakomý R, Vyzula R, Brabec P, Svoboda M, Dušek L and Gregor J: Patients with advanced and metastatic renal cell carcinoma treated with targeted therapy in the Czech Republic: Twenty cancer centres, six agents, one database. Med Oncol. 29:3314–3320. 2012.PubMed/NCBI View Article : Google Scholar
4	Padala SA and Barsouk A, Thandra KC, Saginala K, Mohammed A, Vakiti A, Rawla P and Barsouk A: Epidemiology of renal cell carcinoma. World J Oncol. 11:79–87. 2020.PubMed/NCBI View Article : Google Scholar
5	World Health Organization: Globocan 2020. Cancer Today. Data visualization tools for exploring the global cancer burden in 2020. https://gco.iarc.fr/today/data/factsheets/populations/642-romania-fact-sheets. Accessed August, 2020.
6	Bălan DG, Balcangiu-Stroescu AE, Tănăsescu MD, Diaconescu AC, Răducu L, Mihai A, Tănase M, Stănescu II and Ionescu D: Nutritional intervention in patients with diabetic renal disease-a brief presentation. Rev Chim Buchar. 69:4078–4082. 2018.
7	Măndiță A, Timofte D, Balcangiu-Stroescu AE, Bălan DG, Răducu L, Tănăsescu MD, Diaconescu AC, Dragoș D, Coșconel I and Ionescu D: Treatment of high blood pressure in patients with chronic renal disease. Rev Chim Buchar. 70:993–995. 2019.
8	Totan A, Balcangiu-Stroescu AE, Melescanu Imre M, Miricescu D, Balan DG, Stanescu II, Ionescu D, Timofte D, Tanasescu MD and Greabu M: XOR-possible correlations with oxidative stress and inflammation markers in the context of diabetic kidney disease. Rev Chim Buchar. 70:1396–1398. 2019.
9	Alicic RC, Rooney MT and Tuttle KR: Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 12:2032–2045. 2017.PubMed/NCBI View Article : Google Scholar
10	Disthabanchong S: Vascular calcification in chronic kidney disease: Pathogenesis and clinical implication. World J Nephrol. 6:43–53. 2012.PubMed/NCBI View Article : Google Scholar
11	Timofte D, Ionescu D, Medrihan L, Măndiță A, Rășină A and Damian L: Vascular calcification and bone disease in hemodialysis patients assessment, association and risk factors. Nephrology Dialysis Transplantation; Oxford Univ Press. 22:325–326. 2007.
12	Timofte D, Dragoș D, Balcangiu-Stroescu A, Tănăsescu M, Bălan DG, Răducu L, Tulin A, Stiru O and Ionescu D: Abdominal aortic calcification in predialysis patients: Contribution of traditional and uremia-related risk factors. Exp Ther Med. 20:97–102. 2020.PubMed/NCBI View Article : Google Scholar
13	Timofte D, Măndiță A, Balcangiu-Stroescu AE, Bălan DG, Răducu L, Tănăsescu MD, Diaconescu AC, Dorin D, Coșconel CI and Ionescu D: Hyperuricemia and cardiovascular diseases-clinical and paraclinical correlations. Rev Chim Buchar. 70:1045–1046. 2019.PubMed/NCBI View Article : Google Scholar
14	Epingeac ME, Gaman MA, Diaconu C, Gad M and Gaman AM: The evaluation of oxidative stress in obesity. Rev Chim Buchar. 70:2241–2244. 2019.
15	Diaconu C: Midaortic syndrome in a young man. Cor et Vasa. 59:e171–e173. 2017.
16	Balcangiu-Stroescu AE, Tănăsescu MD, Diaconescu A, Răducu L, Constantin AM, Bălan DG, Țărmure V and Ionescu D: Cardiovascular comorbidities, inflammation and serum albumin levels in a group of hemodialysis patients. Rev Chim Buchar. 69:926–929. 2019.
17	Diaconu C: Treatment of Diabetes in Patients with Heart Failure. The 3rd International Conference on Interdisciplinary Management of Diabetes Mellitus and its Complications-Diabetes Mellitus in Internal Medicine, INTERDIAB 2017 Proceedings. Serafinceanu C, Negoita O and Elian V (eds). Niculescu, Bucharest, pp170-177, 2017.
18	Balcangiu-Stroescu AE, Tănăsescu MD, Diaconescu AC, Răducu L, Bălan DG, Mihai A, Tănase M, Stănescu II and Ionescu D: Diabetic nephropathy: A concise assessment of the causes, risk factors and implications in diabetic patients. Rev Chim Buchar. 69:3118–3121. 2018.
19	Husseinzadeh HD and Garcia JA: Therapeutic rationale for mTOR inhibition in advanced renal cell carcinoma. Curr Clin Pharmacol. 6:214–221. 2011.PubMed/NCBI View Article : Google Scholar
20	Chen H, Zhu D, Zheng Z, Cai Y, Chen Z and Xie W: CEP55 promotes epithelial-mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway. Clin Transl Oncol. 21:939–949. 2019.PubMed/NCBI View Article : Google Scholar
21	Xiang RF, Wang Y, Zhang N, Xu WB, Cao Y, Tong J, Li JM, Wu YL and Yan H: MK2206 enhances the cytocidal effects of bufalin in multiple myeloma by inhibiting the AKT/mTOR pathway. Cell Death Dis. 8(e2776)2017.PubMed/NCBI View Article : Google Scholar
22	Martini M, de Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signalling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014.PubMed/NCBI View Article : Google Scholar
23	Costa RLB, Han HS and Gradishar WJ: Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: A review. Breast Cancer Res Treat. 69:397–406. 2018.PubMed/NCBI View Article : Google Scholar
24	Sathe A and Nawroth R: Targeting the PI3K/AKT/mTOR pathway in bladder cancer. Methods Mol Biol. 1655:335–350. 2018.PubMed/NCBI View Article : Google Scholar
25	O'Donnell JS, Massi D, Teng MW and Mandala M: PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol. 48:91–103. 2018.PubMed/NCBI View Article : Google Scholar
26	Chamcheu JC, Roy T, Uddin MB, Banang-Mbeumi S, Chamcheu RN, Walker AL, Liu YY and Huang S: Role and therapeutic targeting of the PI3K/AKT/mTOR signaling pathway in skin cancer: A review of current status and future trends on natural and synthetic Agents therapy. Cells. 8(803)2019.PubMed/NCBI View Article : Google Scholar
27	Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A and Saki N: Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 72:2337–2347. 2015.PubMed/NCBI View Article : Google Scholar
28	Aggarwal S, John S, Sapra L, Sharma SC and Das SN: Targeted disruption of PI3K/AKT/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells. Cancer Chemother Pharmacol. 83:451–461. 2019.PubMed/NCBI View Article : Google Scholar
29	Li Z, Liu J, Que L and Tang X: The immunoregulatory protein B7-H3 promotes aerobic glycolysis in oral squamous carcinoma via PI3K/AKT/mTOR pathway. J Cancer. 10:5770–5784. 2019.PubMed/NCBI View Article : Google Scholar
30	Graupera M and Potente M: Regulation of angiogenesis by PI3K signaling networks. Exp Cell Res. 319:1348–1355. 2013.PubMed/NCBI View Article : Google Scholar
31	Carnero A, Blanco-Aparicio C, Renner O, Link W and Leal JF: The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 8:187–198. 2008.PubMed/NCBI View Article : Google Scholar
32	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/AKT signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004.PubMed/NCBI View Article : Google Scholar
33	Araki N, Hatae T, Furukawa A and Swanson JA: Phosphoinositide-3-kinase independent contractile activities associated with Fcgamma-receptor-mediated phagocytosis and macropinocytosis in macrophages. J Cell Sci. 116:247–257. 2003.PubMed/NCBI View Article : Google Scholar
34	Zhang J, Yu XH, Yan YG, Wang C and Wang WJ: PI3K/AKT signaling in osteosarcoma. Clin Chim Acta. 444:182–192. 2015.PubMed/NCBI View Article : Google Scholar
35	Regan MM and Phillip AD: AKT-dependent and independent mechanisms of mTOR regulation in cancer. Cell Signal. 21:656–664. 2009.PubMed/NCBI View Article : Google Scholar
36	Sarbassov DD, Guertin DA, Ali SM and Sabatini DM: Phosphorylation and regulation of AKT/PKB by the rictor-mTOR complex. Science. 307:1098–1101. 2005.PubMed/NCBI View Article : Google Scholar
37	Krycer JR, Sharpe LJ, Luu W and Brown AJ: The AKT-SREBP nexus: Cell signaling meets lipid metabolism. Trends Endocrinol Metab. 21:268–276. 2010.PubMed/NCBI View Article : Google Scholar
38	Abeyrathna P and Su Y: The critical role of AKT in cardiovascular function. Vascul Pharmacol. 74:38–48. 2015.PubMed/NCBI View Article : Google Scholar
39	Nicholson KM and Anderson NG: The protein kinase B/AKT signalling pathway in human malignancy. Cell Signal. 14:381–395. 2002.PubMed/NCBI View Article : Google Scholar
40	Brazil DP, Yang ZZ and Hemmings BA: Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci. 29:233–242. 2004.PubMed/NCBI View Article : Google Scholar
41	Hers I, Vincent EE and Tavaré JM: AKT signalling in health and disease. Cell Signal. 23:1515–1527. 2011.PubMed/NCBI View Article : Google Scholar
42	Meric-Bernstam F and Gonzalez-Angulo AM: Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 27:2278–2287. 2009.PubMed/NCBI View Article : Google Scholar
43	JIlha J, Espírito-Santo CC and de Freitas GR: mTOR signaling pathway and protein synthesis: From training to aging and muscle autophagy. Adv Exp Med Bio. 1088:139–151. 2018.PubMed/NCBI View Article : Google Scholar
44	Ayuk SM and Abrahamse H: mTOR signaling pathway in cancer targets photodynamic therapy in vitro. Cells. 8(431)2019.PubMed/NCBI View Article : Google Scholar
45	Battelli C and Cho DC: mTOR inhibitors in renal cell carcinoma. Therapy. 8:359–367. 2011.PubMed/NCBI View Article : Google Scholar
46	Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007.PubMed/NCBI View Article : Google Scholar
47	Saxton RA and Sabatini DM: mTOR signaling in growth, metabolism, and disease. Cell. 168:960–976. 2017.PubMed/NCBI View Article : Google Scholar
48	Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell. 149:274–293. 2012.PubMed/NCBI View Article : Google Scholar
49	Inoki K, Zhu T and Guan KL: TSC2 mediates cellular energy response to control cell growth and survival. Cell. 115:577–590. 2003.PubMed/NCBI View Article : Google Scholar
50	Cornu M, Albert V and Hall MN: mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev. 23:53–62. 2013.PubMed/NCBI View Article : Google Scholar
51	Stallone G, Infante B, Prisciandaro C and Grandaliano G: mTOR and aging: An old fashioned dress. Int J Mol Sci. 20(2774)2019.PubMed/NCBI View Article : Google Scholar
52	Wullschleger K, Loewith R and Hall EB: TOR signaling in growth and metabolism. Cell. 124:471–484. 2006.PubMed/NCBI View Article : Google Scholar
53	Fredrichkson RM, Mushynski WE and Sonenberg N: Phosphorylation of translation initiation factor eIf-4E is induced in a Ras-dependent manner during nerve growth factor-mediated PC 12 cell differentiation. Mol Cell Biol. 12:1239–1247. 1992.PubMed/NCBI View Article : Google Scholar
54	Martin CK and Borden KL: The oncogene eIF4E: Using biochemical insights to target cancer. J Interferon Cytokine Res. 33:227–238. 2013.PubMed/NCBI View Article : Google Scholar
55	Ben-Sahra I, Hoxhaj G, Ricoult SJH, Asara JM and Manning BD: mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science. 351:728–733. 2016.PubMed/NCBI View Article : Google Scholar
56	Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, et al: Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 39:171–183. 2010.PubMed/NCBI View Article : Google Scholar
57	Kim J, Kundu M, Viollet B and Guan KL: AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 13:132–141. 2011.PubMed/NCBI View Article : Google Scholar
58	Tripathi DN, Chowdhury R, Trudel LJ, Tee AR, Slack RS, Walker CL and Wogan GN: Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proc Natl Acad Sci USA. 110:E2950–E2957. 2013.PubMed/NCBI View Article : Google Scholar
59	Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, et al: A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31:1095–1108. 2012.PubMed/NCBI View Article : Google Scholar
60	Zhao J, Zhai B, Gygi SP and Goldberg AL: mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci USA. 112:15790–15797. 2015.PubMed/NCBI View Article : Google Scholar
61	Rousseau A and Bertolotti A: An evolutionarily conserved pathway controls proteasome homeostasis. Nature. 536:184–189. 2016.PubMed/NCBI View Article : Google Scholar
62	Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C and Blenis J: mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4EBP1/eukaryotic translation factor 4E. Mol Cell Biol. 24:200–216. 2004.PubMed/NCBI View Article : Google Scholar
63	Cai H, Dong LQ and Liu F: Recent advances in adipose mTOR signaling and function: Therapeutic prospects. Trends Pharmacol Sci. 37:303–317. 2016.PubMed/NCBI View Article : Google Scholar
64	Inoki K and Guan KL: Complexity of the TOR signaling network. Trends Cell Biol. 16:206–212. 2006.PubMed/NCBI View Article : Google Scholar
65	Kumar A, Kumari N, Gupta V and Prasad R: Renal cell carcinoma: Molecular aspects. Ind J Clin Biochem. 33:246–254. 2018.PubMed/NCBI View Article : Google Scholar
66	Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H and Sawyers CL: Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 98:10314–10319. 2001.PubMed/NCBI View Article : Google Scholar
67	Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA and Lotan T: Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 15:222–234. 2018.PubMed/NCBI View Article : Google Scholar
68	Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H, et al: Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 45:860–867. 2013.PubMed/NCBI View Article : Google Scholar
69	Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT, Moore L, O'Toole T, Gibbons J, Belldegrun AS and Figlin RA: Prognostic relevance of the mTOR pathway in renal cell carcinoma: Implications for molecular patient selection for targeted therapy. Cancer. 109:2257–2267. 2007.PubMed/NCBI View Article : Google Scholar
70	Damayanti NP, Budka JA, Khella HWZ, Ferris MW, Ku SY, Kauffman E, Wood AC, Ahmed K, Chintala VN, Adelaiye-Ogala R, et al: Therapeutic targeting of TFE3/IRS-1/PI3K/mTOR axis in translocation renal cell carcinoma. Clin Cancer Res. 24:5977–5989. 2018.PubMed/NCBI View Article : Google Scholar
71	Brugarolas J: Renal-cell carcinoma-molecular pathways and therapies. N Engl J Med. 356:185–187. 2007.PubMed/NCBI View Article : Google Scholar
72	Robb VA, Karbowniczek M, Klein-Szanto AJ and Henske EP: Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol1. 77:346–352. 2007.PubMed/NCBI View Article : Google Scholar
73	Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ and Abraham RT: Regulation of hypoxia-inducible factor 1a expression and function by the mammalian target of rapamycin. Mol Cell Biol. 22:7004–7014. 2002.PubMed/NCBI View Article : Google Scholar
74	Miikkulainen P, Högel H, Seyednasrollah F, Rantanen K, Elo LL and Jaakkola PM: Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma. J Biol Chem. 294:3760–3771. 2019.PubMed/NCBI View Article : Google Scholar
75	Fiorini C, Massari F, Pedron S, Sanavio S, Ciccarese C, Porcaro AB, Artibani W, Bertoldo F, Zampini C, Sava T, et al: Methods to identify molecular expression of mTOR pathway: A Rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors. Am J Cancer Res. 4:907–915. 2014.PubMed/NCBI
76	Pantuck AJ, Zeng G, Belldegrun AS and Figlin RA: Pathobiology, prognosis, and targeted therapy for renal cell carcinoma: Exploiting the hypoxia-induced pathway. Clin Cancer Res. 9:4641–4652. 2003.PubMed/NCBI
77	Baba M, Hirai S, Yamada-Okabe H, Hamada K, Tabuchi H, Kobayashi K, Kondo K, Yoshida M, Yamashita A, Kishida T, et al: Loss of von Hippel-Lindau protein causes cell density dependent deregulation of cyclinD1 expression through hypoxia-inducible factor. Oncogene. 22:2728–2738. 2003.PubMed/NCBI View Article : Google Scholar
78	Zatyka M, da Silva NF, Clifford SC, Morris MR, Wiesener MS, Eckardt KU, Houlston RS, Richards FM, Latif F and Maher ER: Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res. 62:3803–3811. 2002.PubMed/NCBI
79	Toschini A, Edelstein J, Rockwell P, Ohh M and Foster DA: HIF alpha expression in HVL-deficient renal cancer cells is dependent on phospholipase D. Oncogene. 27:2746–2753. 2008.PubMed/NCBI View Article : Google Scholar
80	Carew JS, Kelly KR and Nawrocki ST: Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol. 6:17–22. 2011.PubMed/NCBI View Article : Google Scholar
81	Pal SK and Quinn DI: Differentiating mTOR inhibitors in renal cell carcinoma. Cancer Treat Rev. 39:709–719. 2013.PubMed/NCBI View Article : Google Scholar
82	Konings IR, Verweij J, Wiemer EA and Sleijfer S: The applicability of mTOR inhibition in solid tumors. Curr Cancer Drug Targets. 9:439–450. 2009.PubMed/NCBI View Article : Google Scholar
83	Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, et al: Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet. 372:449–56. 2008.PubMed/NCBI View Article : Google Scholar
84	Bedke J, Gauler T, Grünwald V, Hegele A, Herrmann E, Hinz S, Janssen J, Schmitz S, Schostak M, Tesch H, et al: Systemic therapy in metastatic renal cell carcinoma. World J Urol. 35:179–188. 2017.PubMed/NCBI View Article : Google Scholar
85	Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 356:2271–2281. 2007.PubMed/NCBI View Article : Google Scholar
86	Park I, Lee SH and Lee JL: A Multicenter phase II trial of axitinib in patients with recurrent or metastatic non-clear-cell renal cell carcinoma who had failed prior treatment with Temsirolimus. Clin Genitourin Cancer. 16:e997–e1002. 2018.PubMed/NCBI View Article : Google Scholar
87	Tegos T, Tegos K, Dimitriadou A and Dimitriadis G: Current and emerging first-line systemic therapies in metastatic clear-cell renal cell carcinoma. J BUON. 24:1340–1353. 2019.PubMed/NCBI
88	Ye X, Ruan JW, Huang H, Huang WP, Zhang Y and Zhang F: PI3K-AKT-mTOR inhibition by GNE-477 inhibits renal cell carcinoma cell growth in vitro and in vivo. Aging (Albany NY). 12:9489–9499. 2020.PubMed/NCBI View Article : Google Scholar