Phosphorylation of Protein Kinase Akt by Mtorc2 in Peripheral Blood Mononuclear Cells of Patients with Cancer and Diabetes

Authors

  • Tamara Sergeevnа Vatseba SHEE "Ivano-Frankivsk National Medical University», Ivano-Frankivsk, Ukraine.
  • Liubov Konstantinovna Sokolova SI "V.P. Komisarenko Institute of Endocrinology and Metabolism "
  • Victor Volodymyrovich Pushkarev SI "V.P. Komisarenko Institute of Endocrinology and Metabolism "
  • Olena Igorevna Kovzun SI "V.P. Komisarenko Institute of Endocrinology and Metabolism "
  • Vladimir Mikhailovich Pushkarev SI "V.P. Komisarenko Institute of Endocrinology and Metabolism "
  • Bogdan Bogdanovich Guda SI "V.P. Komisarenko Institute of Endocrinology and Metabolism "
  • Mykola Dmytrovich Tronko SI "V.P. Komisarenko Institute of Endocrinology and Metabolism "

DOI:

https://doi.org/10.30564/jer.v1i1.674

Abstract

Akt/mTOR/p70S6K1 signaling pathway plays an important role in the pathogenesis of cancer and diabetes. Macrophages and lymphocytes are involved in the pathogenesis of diabetes, diabetic atherosclerosis, formation of insulin resistance as well as immune response to cancer and tumor maintenance. The aim of the study was to determine the Akt activation by mTORC2 in peripheral blood mononuclear cell (PBMC) of patients with type 2 diabetes and cancer. The following groups were studied: control group, patients with type 2 diabetes, cancer patients and patients with both cancer and diabetes. The amounts of phospho-Akt (рS473) and phospho-p70S6K1 (p-T389) were determined using ELISA kits. The amount of phosphorylated Akt significantly increases in PBMC of patients with cancer. There was no effect in PBMC from patients with type 2 diabetes and significant decrease in the amount of phospho-Akt in PBMC of the patients group both with cancer and diabetes. p70S6K1 activation was observed in PBMC of the groups 2 and 3 patients. Thus, chronic diseases such as type 2 diabetes and cancer can affect the signaling mechanisms in blood cells. The state of Akt phosphorylation in leukocytes can indicate the activity of mTORC1 and its substrates, which may be important for the evaluation of the pathological process and the efficacy of the drugs.

Keywords:

Akt, mTORC2, P70S6K1, Peripheral blood mononuclear cell, Cancer, Diabetes

References

[1] Manning BD, Toker A. AKT/PKB Signaling: Navigating the Network [J]. Cell. 2017, 169: 381-405.

[2] de Oliveira CE, Oda JM, Losi Guembarovski R, de Oliveira KB, Ariza CB, Neto JS, Banin Hirata BK, Watanabe MA. CC chemokine receptor 5: the interface of host immunity and cancer [J]. Dis Markers. 2014, 2014: 126954. DOI: 10.1155/2014/126954

[3] Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, Sautès-Fridman C, Ma Y, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer [J]. Oncoimmunology.2012, 1(8): 1323-1343.

[4] Tronko ND, Pushkarev VM, Sokolova LK, Pushkarev VV, Kovzun OI. Molecular mechanisms of pathogenesis of diabetes and its complications [M]. K.: Publishing house Medkniga, 2018: 264 (In Russian).

[5] Dituri F, Mazzocca A, Giannelli G, Antonaci S. PI3K functions in cancer progression, anticancer immunity and immune evasion by tumors [J]. Clin Dev Immunol. 2011, 2011: 947858. DOI: 10.1155/2011/947858

[6] Covarrubias AJ, Aksoylar HI, Horng T. Control of macrophage metabolism and activation by mTOR and Akt signaling [J]. Semin Immunol. 2015, 27(4): 286-296. DOI: 10.1016/j.smim.2015.08.001

[7] Covarrubias AJ, Aksoylar HI, Yu J, Snyder NW, Worth AJ, Iyer SS, Wang J, Ben-Sahra I, Byles V, Polynne-Stapornkul T, Espinosa EC, Lamming D, Manning BD, Zhang Y, Blair IA, Horng T. AktmTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation [J]. Elife. 2016, 5: e11612. DOI: 10.7554/eLife.11612

[8] Kim LC, Cook RS, Chen J. mTORC1 and mTORC2 in cancer and the tumor microenvironment [J]. Oncogene. 2017, 36(16): 2191-2201. DOI: 10.1038/onc.2016.363

[9] Puskarev VM, Sokolova LK, Pushkarev VV, Tronko ND. The role of AMPK and mTOR in the development of insulin resistance and type 2 diabetes. The mechanism of metformin action [J]. Probl Endocr Pathol. 2016, 3: 77-90. (In Russian).

[10] Sokolova LK, Pushkarev VM, Belchina YB, Pushkarev VV, Tronko ND. Effect of combined treatment with insulin and metformin on 5′AMP-activated protein kinase activity in lymphocytes of diabetic patients [J]. Rep Nat Acad Sci Ukr. 2018, 5: 100-104. DOI: https://doi.org/10.15407/dopovidi2018.05.100

[11] Zhang Z, Amorosa LF, Coyle SM, Macor MA, Birnbaum MJ, Lee LY, Haimovich B. Insulin-dependent regulation of mTORC2-Akt-FoxO suppresses TLR4 signaling in human leukocytes: relevance to type 2 diabetes [J]. Diabetes. 2016, 65(8): 2224-2234. DOI: 10.2337/db16-0027

[12] Zhang Z, Amorosa LF, Coyle SM, Macor MA, Lubitz SE, Carson JL, Birnbaum MJ, Lee LY, Haimovich B. Proteolytic cleavage of AMPKα and intracellular MMP9 expression are both required for TLR4-mediated mTORC1 activation and HIF-1α expression in leukocytes. J Immunol [J]. 2015, 195(5): 2452-2460. DOI: 10.4049/jimmunol.1500944

[13] Banerjee D, Sinha A, Saikia S, Gogoi B, Rathore AK, Das AS, Pal D, Buragohain AK, Dasgupta S. Inflammation-induced mTORC2-Akt-mTORC1 signaling promotes macrophage foam cell formation [J]. Biochimie. 2018, 151: 139-149. DOI: 10.1016/j.biochi.2018.06.001

[14] Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities [J]. Nat Rev Drug Discov. 2014, 13: 140-156.

[15] Xu Z, Hu J, Cao H, Pilo MG, Cigliano A, Shao Z, Xu M, Ribback S, Dombrowski F, Calvisi DF, Chen X. Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2pathway [J]. Exp Mol Med. 2018, 50(1): e417. DOI: 10.1038/emm.2017.158

[16] Ebner M, Sinkovics B, Szczygieł M, Ribeiro DW, Yudushkin I. Localization of mTORC2 activity inside cells [J]. J Cell Biol. 2017, 216(2): 343-353 DOI: 10.1083/jcb.201610060

[17] Jhanwar-Uniyal M, Amin AG, Cooper JB, Das K, Schmidt M, Murali R. Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects [J]. Adv Biol Regul. 2017, 64: 39-48. DOI: 10.1016/j.jbior.2016.12.001

[18] Huang SC, Smith AM, Everts B, Colonna M, Pearce EL, Schilling JD, Pearce EJ. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation [J]. Immunity. 2016, 45(4): 817-830. DOI: 10.1016/j.immuni.2016.09.016

[19] Shrivastava R, Asif M, Singh V, Dubey P, Ahmad Malik S, Lone MU, Tewari BN, Baghel KS, Pal S,Nagar GK, Chattopadhyay N, Bhadauria S. M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis [J]. Cytokine. 2018: S1043-4666(18)30118-2. DOI: 10.1016/j.cyto.2018.03.032

[20] Altomare DA, Testa JR. FRAP1 (FK506 binding protein 12-rapamycin associated protein 1) [J]. Atlas Genet Cytogenet Oncol Haematol. 2009, 13(5); 348- 353.

[21] Pushkarev VM, Sokolova LK, Pushkarev VV, Tronko MD. Biochemical mechanisms connecting diabetes and cancer. Effects of metformin [J]. Endokrynologia. 2018, 23(2): 167-179. (In Russian).

[22] Salazar M, Lorente M, García-Taboada E, Gómez EP, Dávila D, Zúñiga-García P, Flores JM, Rodríguez A, Hegedus Z, Mosén-Ansorena D, Aransay AM, Hernández-Tiedra S, López-Valero I, Quintanilla M, Sánchez C, Iovanna JL, Dusetti N, Guzmán M, Francis SE, Carracedo A, Kiss-Toth E, Velasco G. TRIB3 suppresses tumorigenesis by controlling mTORC2/ AKT/FOXO signaling [J]. Mol Cell Oncol. 2015, 2(3): e980134. DOI: 10.4161/23723556.2014.980134

[23] Dan HC, Antonia RJ, Baldwin AS. PI3K/Akt promotes feedforward mTORC2 activation through IKKα [J]. Oncotarget. 2016, 7(16): 21064-21075. DOI: 10.18632/oncotarget.8383

[24] Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis [J]. Cytokine. 2017, 89: 127-135. DOI: 10.1016/j.cyto.2016.01.021

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Vatseba, T. S., Sokolova, L. K., Pushkarev, V. V., Kovzun, O. I., Pushkarev, V. M., Guda, B. B., & Tronko, M. D. (2019). Phosphorylation of Protein Kinase Akt by Mtorc2 in Peripheral Blood Mononuclear Cells of Patients with Cancer and Diabetes. Journal of Endocrinology Research, 1(1), 8–12. https://doi.org/10.30564/jer.v1i1.674

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