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Assessment of AKT/mTOR Signaling Pathway Components in Kidney Cancers and Their Connection with Metastases

Assessment of AKT/mTOR Signaling Pathway Components in Kidney Cancers and Their Connection with Metastases

Spirina L.V., Usynin E.A., Yurmazov Z.A., Kondakova I.V., Slonimskaya E.M.
Key words: kidney cancer; AKT/mTOR signaling pathway; mTOR; PTEN phosphatase; AKT; GSK-3beta; PDK1; c-RAF; p70 S6 kinase; 4E-BP1.
2019, volume 11, issue 4, page 74.

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The aim of the study was to assess gene expression of the AKT/mTOR signaling pathway components in the molecular mechanisms of kidney cancer development and progression.

Material and Methods. The subject of the study was a tumor and non-transformed tissue of 34 patients with clear cell kidney cancer T13N01M01. The mRNA level of PTEN, AKT, GSK-3beta, PDK1, c-RAF, mTOR, p70 S6 kinase, 4E-BP1 was studied by real-time PCR, the content of the parameters studied was determined by Western blotting.

Results. The AKT, PTEN mRNA levels, and the protein content were associated with the development of hematogenous metastasis. The increase of AKT content and expression is associated with the decrease in mRNA and protein level of PTEN phosphatase. The specificity of mRNA translation in the tumor tissue has been shown to determine the development of the disease as well. The correlation analysis did not find direct relationship between the level of expression of the studied genes and their protein products.

Conclusion. Molecular mechanisms of tumor progression are associated with gene expression and protein content. The change in AKT, PTEN, 4E-BP1, and GSK-3beta mRNA levels has been found to lead to the development of a metastatic process in kidney cancer.

  1. Spirina L.V., Usynin E.A., Kondakova I.V., Yurmazov Z.A., Slonimskaya E.M. Effect of target therapy on the content of transcription and growth factors, protein kinase TOR, and activity of intracellular proteases in patients with metastatic renal cell carcinoma. Bull Exp Biol Med 2016; 160(6): 798–801, https://doi.org/10.1007/s10517-016-3313-6.
  2. Hager M., Haufe H., Alinger B., Kolbitsch C. pS6 expression in normal renal parenchyma, primary renal cell carcinomas and their metastases. Pathol Oncol Res 2012; 18(2): 277–283, https://doi.org/10.1007/s12253-011-9439-y.
  3. Hudson C.C., Liu M., Chiang G.G., Otterness D.M., Loomis D.C., Kaper F., Giaccia A.J., Abraham R.T. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22(20): 7004–7014, https://doi.org/10.1128/mcb.22.20.7004-7014.2002.
  4. Pópulo H., Lopes J.M., Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012; 13(2): 1886–1918, https://doi.org/10.3390/ijms13021886.
  5. Li J., Lu Y., Akbani R., Ju Z., Roebuck P.L., Liu W., Yang J.Y., Broom B.M., Verhaak R.G., Kane D.W., Wakefield C., Weinstein J.N., Mills G.B., Liang H. TCPA: a resource for cancer functional proteomics data. Nat Methods 2013; 10(11): 1046–1047, https://doi.org/10.1038/nmeth.2650.
  6. Gao T., Furnari F., Newton A.C. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 2005; 18(1): 13–24, https://doi.org/10.1016/j.molcel.2005.03.008.
  7. Nishikawa M., Miyake H., Harada K., Fujisawa M. Expression of molecular markers associated with the mammalian target of rapamycin pathway in nonmetastatic renal cell carcinoma: effect on prognostic outcomes following radical nephrectomy. Urol Oncol 2014; 32(1): 15–21, https://doi.org/10.1016/j.urolonc.2013.07.014.
  8. Dodd K.M., Yang J., Shen M.H., Sampson J.R., Tee A.R. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 2015; 34(17): 2239–2250, https://doi.org/10.1038/onc.2014.164.
  9. Figlin R.A., Kaufmann I., Brechbiel J. Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors. Int J Cancer 2013; 133(4): 788–796, https://doi.org/10.1002/ijc.28023.
  10. Oeckinghaus A., Postler T.S., Rao P., Schmitt H., Schmitt V., Grinberg-Bleyer Y., Kühn L.I., Gruber C.W., Lienhard G.E., Ghosh S. κB-Ras proteins regulate both NF-κB-dependent inflammation and Ral-dependent proliferation. Cell Rep 2014; 8(6): 1793–1807, https://doi.org/10.1016/j.celrep.2014.08.015.
  11. Thangavelu K., Pan C.Q., Karlberg T., Balaji G., Uttamchandani M., Suresh V., Schüler H., Low B.C., Sivaraman J. Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. Proc Natl Acad Sci U S A 2012; 109(20): 7705–7710, https://doi.org/10.1073/pnas.1116573109.
  12. Gerlinger M., Rowan A.J., Horswell S., Math M., Larkin J., Endesfelder D., Gronroos E., Martinez P., Matthews N., Stewart A., Tarpey P., Varela I., Phillimore B., Begum S., McDonald N.Q., Butler A., Jones D., Raine K., Latimer C., Santos C.R., Nohadani M., Eklund A.C., Spencer-Dene B., Clark G., Pickering L., Stamp G., Gore M., Szallasi Z., Downward J., Futreal P.A., Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366(10): 883–892, https://doi.org/10.1056/nejmoa1113205.
  13. Quintayo M.A., Munro A.F., Thomas J., Kunkler I.H., Jack W., Kerr G.R., Dixon J.M., Chetty U., Bartlett J.M. GSK3β and cyclin D1 expression predicts outcome in early breast cancer patients. Breast Cancer Res Treat 2012; 136(1): 161–168, https://doi.org/10.1007/s10549-012-2229-8.
  14. Almatore D.A., Tesla J.R. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005; 24(50): 7455–7464, https://doi.org/10.1038/sj.onc.1209085.
  15. Darwish O.M., Kapur P., Youssef R.F., Bagrodia A., Belsante M., Alhalabi F., Sagalowsky A.I., Lotan Y., Margulis V. Cumulative number of altered biomarkers in mammalian target of rapamycin pathway is an independent predictor of outcome in patients with clear cell renal cell carcinoma. Urology 2013; 81(3): 581–586, https://doi.org/10.1016/j.urology.2012.11.030.
  16. Spirina L.V., Usynin E.A., Kondakova I.V., Yurmazov Z.A., Slonimskaya E.M., Kolegova E.S. Activation of AKT of signaling pathway and the level of mTOR substrates in tumor of patients with kidney cancer, connection with prevalence of malignancy. Voprosy onkologii 2016; 62(3): 490–494.
  17. Lidgren A., Bergh A., Grankvist K., Lindh G., Ljungberg B. Hypoxia-inducible factor-1α mRNA and protein levels in renal cell carcinoma. J Cancer Mol 2008; 4(5): 153–157.
  18. Yurmazov Z.A., Usynin E.A., Kondakova I.V., Slonimskaya E.M., Spirina L.V. Association of cancer molecular parameters with effectiveness of pazopanib treatment in advanced kidney cancer patients. Molekulyarnaya meditsina 2015; 6: 61–66.
  19. Akbani R., Ng P.K., Werner H.M., Shahmoradgoli M., Zhang F., Ju Z., Liu W., Yang J.Y., Yoshihara K., Li J., Ling S., Seviour E.G., Ram P.T., Minna J.D., Diao L., Tong P., Heymach J.V., Hill S.M., Dondelinger F., Städler N., Byers L.A., Meric-Bernstam F., Weinstein J.N., Broom B.M., Verhaak R.G., Liang H., Mukherjee S., Lu Y., Mills G.B. A pan-cancer proteomic perspective on The Cancer Genome Atlas. Nat Commun 2014; 5: 3887, https://doi.org/10.1038/ncomms4887.
  20. Lolkema M.P., Mans D.A., Ulfman L.H., Volpi S., Voest E.E., Giles R.H. Allele-specific regulation of primary cilia function by the von Hippel-Lindau tumor suppressor. Eur J Hum Genet 2008; 16(1): 73–78, https://doi.org/10.1038/sj.ejhg.5201930.
  21. Mendoza M.C., Er E.E., Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 2011; 36(6): 320–328, https://doi.org/10.1016/j.tibs.2011.03.006.
  22. Schultz L., Chaux A., Albadine R., Hicks J., Kim J.J., De Marzo A.M., Allaf M.E., Carducci M.A., Rodriguez R., Hammers H.J., Argani P., Reuter V.E., Netto G.J. Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. Am J Surg Pathol 2011; 35(10): 1549–1556, https://doi.org/10.1097/pas.0b013e31822895e5.
  23. Yu S., Hou Q., Sun H., Liu J., Li J. Upregulation of C-C chemokine receptor type 7 expression by membrane-associated prostaglandin E synthase-1/prostaglandin E2 requires glycogen synthase kinase 3β-mediated signal transduction in colon cancer cells. Mol Med Rep 2015; 12(5): 7169–7175, https://doi.org/10.3892/mmr.2015.4290.
  24. Greenbaum D., Colangelo C., Williams K., Gerstein M. Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003; 4(9): 117, https://doi.org/10.1186/gb-2003-4-9-117.
  25. Han G., Zhao W., Song X., Kwok-Shing Ng P., Karam J.A., Jonasch E., Mills G.B., Zhao Z., Ding Z., Jia P. Unique protein expression signatures of survival time in kidney renal clear cell carcinoma through a pan-cancer screening. BMC Genomics 2017; 18(Suppl 6): 678, https://doi.org/10.1186/s12864-017-4026-6.
  26. Guo H., German P., Bai S., Barnes S., Guo W., Qi X., Lou H., Liang J., Jonasch E., Mills G.B., Ding Z. The PI3K/AKT Pathway and Renal Cell Carcinoma. J Genet Genomics 2015; 42(7): 343–353, https://doi.org/10.1016/j.jgg.2015.03.003.
Spirina L.V., Usynin E.A., Yurmazov Z.A., Kondakova I.V., Slonimskaya E.M. Assessment of AKT/mTOR Signaling Pathway Components in Kidney Cancers and Their Connection with Metastases. Sovremennye tehnologii v medicine 2019; 11(4): 74, https://doi.org/10.17691/stm2019.11.4.08


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