TSitologiya i Genetika 2019, vol. 53, no. 6, 64-70
Cytology and Genetics 2019, vol. 53, no. 6, 489–493, doi: https://www.doi.org/10.3103/S0095452719060112

Activation of the PI3K/Akt/mTOR/p70S6K1 signaling cascade in peripheral blood mononuclear cells. Association with insulin and insulin-like growth factor levels in the blood of cancer patients and diabetes

Vatseba T.S., Sokolova L.K., Pushkarev V.V., Kovzun O.I., Guda B.B., Pushkarev V.M., Tronko M.D.

SUMMARY. The aim of the work was to determine the content of insulin and insulin-like growth factor (IGF-1) in the blood in association with the activity of the end units of the PІ3K/Akt/mTORC1/p70S6K cascade in peripheral blood mononuclear cells (PMBC) of patients with type 2 diabetes (T2D) and cancer. The level of insulin and IGF-1 in the blood and the phosphorylation of Akt (Ser473), p70S6K (Thr389) in PMBC were studied by enzyme immunoassay in the following groups: 1 – control
group – healthy people, representative by age; 2 – patients with T2D; 3 – cancer patients; 4 – cancer patients with T2D. It was shown that in the blood of patients with T2D, as well as T2D and cancer (group 4), the level of insulin is markedly increased. The IGF-1 content is significantly higher in cancer patients. Akt and p70S6K phosphorylation increases in cancer patients which indicates the activation of these protein kinases. The mechanisms linking Akt and p70S6K activation in PMBC with insulin and IGF-1 level in the blood of patients with cancer and diabetes are discussed.

Keywords: peripheral blood mononuclear cells, Akt, p70S6K, insulin, insulin-like growth factor, type 2 diabetes, cancer

TSitologiya i Genetika
2019, vol. 53, no. 6, 64-70

Current Issue
Cytology and Genetics
2019, vol. 53, no. 6, 489–493,
doi: 10.3103/S0095452719060112

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References

1. Yang, J., Nishihara, R., Zhang, X., Ogino, S., and Qian, Z.R., Energy sensing pathways: bridging type 2 diabetes and colorectal cancer?, J. Diabetes Complications, 2017, vol. 31, no. 7, pp. 1228–1236.

2. Senovilla, L., Vacchelli, E., Galon, J., Adjemian, S., Eggermont, A., Fridman, W.H., Sautes-Fridman, C., Ma, Y., Tartour, E., Zitvogel, L., Kroemer, G., and Galluzzi, L., Trial watch: prognostic and predictive value of the immune infiltrate in cancer, Oncoimmunology, 2012, vol. 1, no. 8, pp. 1323–1343.

3. de Oliveira, C.E., Oda, J.M., Losi Guembarovski R., de Oliveira K.B., Ariza C.B., Neto J.S., Banin Hirata, B.K., and Watanabe, M.A., CC chemokine receptor 5: the interface of host immunity and cancer, Dis. Markers, 2014, vol. 2014, 126954. https://doi.org/10.1155/2014/126954

4. Sokolova, L.K., Pushkarev, V.M., Pushkarev, V.V., and Tronko, N.D., Diabetes and atherosclerosis. Cellular mechanisms of pathogenesis, Endokrinologia, 2017, vol. 22, no. 2, pp. 127–138.

5. Dituri, F., Mazzocca, A., Giannelli, G., and Antonaci, S., PI3K functions in cancer progression, anticancer immunity and immune evasion by tumors, Clin. Dev. Immunol., 2011, vol. 2011, 947858. https://doi.org/10.1155/2011/947858

6. Tronko, N.D., Pushkarev, V.M., Sokolova, L.K., Pushkarev, V.V., and Kovzun, O.I., Molecular Mechanisms of Pathogenesis of Diabetes and Its Complications, Kyiv: Publishing house Medkniga, 2018, 264 p.

7. Cai, W., Sakaguchi, M., Kleinridders, A., Gonzalez-Del Pino, G., Dreyfuss, J.M., O’Neill, B.T., Ramirez, A.K., Pan, H., Winnay, J.N., Boucher, J., Eck, M.J., and Kahn, C.R., Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression, Nat. Commun., 2017, vol. 8, 14892.

8. Bowers, L.W., Rossi, E.L., O’Flanagan, C.H., de Graffenried, L.A., and Hursting, S.D., The role of the insulin/IGF system in cancer: lessons learned from clinical trials and the energy balance-cancer link, Front. Endocrinol. (Lausanne), 2015, vol. 6, p. 77. https://doi.org/10.3389/fendo.2015.00077

9. Pollak, M., The insulin and insulin-like growth factor receptor family in neoplasia: an update, Nat. Rev. Cancer, 2012, vol. 12, no. 3, pp. 159–169. https://doi.org/10.1038/nrc3215

10. Yoneyama, Y., Inamitsu, T., Chida, K., Iemura, S.I., Natsume, T., Maeda, T., Hakuno, F., and Takahashi, S.I., Serine phosphorylation by mTORC1 promotes IRS-1 degradation through SCFβ-TRCP E3 ubiquitin ligase, iScience, 2018, vol. 5, pp. 1–18. https://doi.org/10.1016/j.isci.2018.06.006

11. Pushkarev, V.M., Sokolova, L.K., Pushkarev, V.V., and Tronko, M.D., The role of AMPK and mTOR in the development of insulin resistance and type 2 diabetes. The mechanism of metformin action (literature review), Probl. Endocrin. Pathol. 2016, vol. 3, pp. 77–90.

12. Copps, K.D., Hancer, N.J., Qiu, W., and White, M.F., Serine 302 phosphorylation of mouse insulin receptor substrate 1 (IRS1) is dispensable for normal insulin signaling and feedback regulation by hepatic S6 kinase, J. Biol. Chem., 2016, vol. 291, no. 16, pp. 8602–8617. https://doi.org/10.1074/jbc.M116.714915

13. Copps, K.D. and White, M.F., Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2, Diabetologia, 2012, vol. 55, no. 10, pp. 2565–2582. https://doi.org/10.1007/s00125-012-2644-8

14. Rad, E., Murray, J.T., and Tee, A.R., Oncogenic signalling through mechanistic target of rapamycin (mTOR): a driver of metabolic transformation and cancer progression, Cancers (Basel), 2018, vol. 10, no. 1, pp. E5. https://doi.org/10.3390/cancers10010005

15. Jhanwar-Uniyal, M., Amin, A.G., Cooper, J.B., Das, K., Schmidt, M.H., and Murali, R., Discrete signaling mechanisms of mTORC1 and mTORC2: connected yet apart in cellular and molecular aspects, Adv. Biol. Regul., 2017, vol. 64, pp. 39–48. https://doi.org/10.1016/j.jbior.2016.12.001

16. Solarek, W., Czarnecka, A.M., Escudier, B., Bielecka, Z.F., Lian, F., and Szczylik, C., Insulin and IGFs in renal cancer risk and progression, Endocr. Relat. Cancer, 2015, vol. 22, no. 5, pp. R253–R264.

17. Pushkarev, V.M., Sokolova, L.K., Pushkarev, V.V., and Tronko, M.D., Biochemical mechanisms connecting diabetes and cancer. Effects of metformin, Endokrinologia, 2018, vol. 23, no. 2, pp. 167–179.

18. Alemán, J.O., Eusebi, L.H., Ricciardiello, L., Patidar, K., Sanyal, A.J., and Holt, P.R., Mechanisms of obesity-induced gastrointestinal neoplasia, Gastroenterology, 2014, vol. 146, pp. 357–373. https://doi.org/10.1053/j.gastro.2013.11.051

19. Arnaldez, F.I. and Helman, L.J., Targeting the insulin growth factor receptor 1, Hematol. Oncol. Clin. North Am., 2012, vol. 26, no. 3, pp. 527–542. doi https://doi.org/10.1016/j.hoc.2012.01.004

20. Yang, Y. and Yee, D., Targeting insulin and insulin-like growth factor signaling in breast cancer, J. Mammary Gland Biol. Neoplasia, 2012, vol. 17, nos. 3–4, pp. 251–261. https://doi.org/10.1007/s10911-012-9268-y

21. Brick, D.J., Gerweck, A.V., Meenaghan, E., Lawson, E.A., Misra, M., Fazeli, P., Johnson, W., Klibanski, A., and Miller, K.K., Determinants of IGF1 and GH across the weight spectrum: from anorexia nervosa to obesity, Eur. J. Endocrinol., 2010, vol. 163, pp. 185–191.

22. Klement, R.J. and Fink, M.K., Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer, Oncogenesis, 2016, vol. 5. e193. https://doi.org/10.1038/oncsis.2016.2

23. Fine, E.J. and Feinman, R.D., Insulin, carbohydrate restriction, metabolic syndrome and cancer, Exp. Rev. Endocrin. Metab., 2014, vol. 10, pp. 15–24.

24. Subramanian, V. and Ferrante, A.W., Obesity, inflammation, and macrophages, Nestle Nutr. Workshop Ser. Pediatr. Program., 2009, vol. 63, pp. 151–159.

25. Menck, K., Behme, D., Pantke, M., Reiling, N., Binder, C., Pukrop, T., and Klemm, F., Isolation of human monocytes by double gradient centrifugation and their differentiation to macrophages in teflon-coated cell culture bags, J. Vis. Exp., 2014, vol. 91. e51554. https://doi.org/10.3791/51554(2014)