Ukr.Biochem.J. 2020; Volume 92, Issue 6, Nov-Dec, pp. 113-118

doi: https://doi.org/10.15407/ubj92.06.113

Activation of the PI3K/AKT/MTOR/P70S6K1 signaling cascade in peripheral blood mononuclear cells in patients with type 2 diabetes

17.12.2020   Uncategorized   No comments

T. S. Vatseba1*, L. K. Sokolova2, V. M. Pushkarev2,
O. I. Kovzun2, B. B. Guda2, V. V. Pushkarev2,
M. D. Tronko2, N. V. Skrypnyk1, L. M. Zaiats1

1Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine;
2SI “V.P. Komisarenko Institute of Endocrinology and Metabolism of NAMS of Ukraine”, Kyiv;
*e-mail: tamara.vatseba@gmail.com

Received: 17 April 2020; Accepted: 13 November 2020

Modern research shows that patients with diabetes mellitus have an increased risk of cancer. PI3K/Akt/mTOR/p70S6K1 signaling pathway plays an important role in the pathogenesis of cancer and diabetes. The aim of this study was to determine the state of РІ3K/Akt/mTORC1/p70S6K signaling cascade activity in peripheral mononuclear blood cells (PBMC) of patients with type 2 diabetes (T2D) relatively to the insulin and insulin-like growth factor (IGF-1) concentrations in blood plasma. Enzyme-linked immunosorbent assay was used to examine the levels of insulin and IGF-1 in blood plasma as well as the content of phosphorylated forms of Akt (Ser473), PRAS40 (Thr246), and p70S6K (Thr389) in PMBC. It was shown that in the blood plasma of patients with T2D the levels of insulin and IGF-1 were increased. Phosphorylation and activation of Akt by the mTORC2 protein kinase complex was not observed. At the same time, the relative degree of phosphorylation of mTORC1 inhibitor, PRAS40, and its substrate, p70S6K, was higher in PMBC of T2D patients in comparison with control values. These data suggest that phosphoinositide-dependent protein kinase 1 (PDK1) and, possibly, mitogen-activated protein kinase (MAPK) could mediate the effects of IGF-1 on Akt activation under type 2 diabetes.

Keywords: , , , , , ,

References:

  1. Vatseba TS. Cancer of the organs of the reproductive system in women with type 2 diabetes. Effects of antidiabetic therapy. Wiad Lek. 2020;73(5):967-971. PubMed, CrossRef
  2. Harding JL, Shaw JE, Peeters A, Cartensen B, Magliano DJ. Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care. 2015;38(2):264-270. PubMed, CrossRef
  3. Jhanwar-Uniyal M, Amin AG, Cooper JB, Das K, Schmidt MH, Murali R. Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects. Adv Biol Regul. 2017;64:39-48. PubMed, CrossRef
  4. Manning BD, Toker A. AKT/PKB Signaling: Navigating the Network. Cell. 2017;169(3):381-405. PubMed, PubMedCentral, CrossRef
  5. Dituri F, Mazzocca A, Giannelli G, Antonaci S. PI3K functions in cancer progression, anticancer immunity and immune evasion by tumors. Clin Dev Immunol. 2011;2011:947858. PubMed, PubMedCentral, CrossRef
  6. Tronko ND, Pushkarev VM, Sokolova LK, Pushkarev VV, Kovzun EI. Molecular mechanisms of the pathogenesis of diabetes mellitus and its complications. K.: Publishing house “Medkniga”. 2018, 264 p. (In Russian).
  7. Alderete TL, Byrd-Williams CE, Toledo-Corral CM, Conti DV, Weigensberg MJ, Goran MI. Relationships between IGF-1 and IGFBP-1 and adiposity in obese African-American and Latino adolescents. Obesity (Silver Spring). 2011;19(5):933-938.  PubMed, PubMedCentral, CrossRef
  8. Pushkarev VM, Sokolova LK, Pushkarev VV, Tronko MD. Biochemical mechanisms connecting diabetes and cancer. Effect of metformin. Endokrynologia. 2018; 23(2):167-179. (In Ukrainian).
  9. Semple RK. EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons. Eur J Endocrinol. 2016;174(5):R209-R223. PubMed, CrossRef
  10. Gristina V, Cupri MG, Torchio M, Mezzogori C, Cacciabue L, Danova M. Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links. Biomed Rep. 2015;3(2):131-136. PubMed, PubMedCentral, CrossRef
  11. Ong PS, Wang LZ, Dai X, Tseng SH, Loo SJ, Sethi G. Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Front Pharmacol. 2016;7:395. PubMed, PubMedCentral, CrossRef
  12. Vadlakonda L, Dash A, Pasupuleti M, Kumar KA, Reddanna P. The Paradox of Akt-mTOR Interactions. Front Oncol. 2013;3:165. PubMed, PubMedCentral, CrossRef
  13. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL.  Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 2008;27(14):1919-1931. PubMed, PubMedCentral, CrossRef
  14. Breuleux M, Klopfenstein M, Stephan C, Doughty CA, Barys L, Maira SM, Kwiatkowski D, Lane HA. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther. 2009;8(4):742-753. PubMed, PubMedCentral, CrossRef
  15. Pushkarev VM, Sokolova LK, Pushkarev VV, Tronko MD. 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;(3):77-90. (In Russian).
  16. Lv D, Guo L, Zhang T, Huang L. PRAS40 signaling in tumor. Oncotarget. 2017;8(40):69076-69085. PubMed, PubMedCentral, CrossRef
  17. Wang H, Zhang Q, Wen Q, Zheng Y, Lazarovici P, Jiang H, Lin J, Zheng W. Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway. Cell Signal. 2012;24(1):17-24.  PubMed, CrossRef
  18. Wiza C, Chadt A, Blumensatt M, Kanzleiter T, Herzfeld De Wiza D, Horrighs A, Mueller H, Nascimento EB, Schürmann A, Al-Hasani H, Ouwens DM. Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle. Arch Physiol Biochem. 2014;120(2):64-72. PubMed, CrossRef
  19. Yoon MS. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients. 2017;9(11):1176. PubMed, PubMedCentral, CrossRef
  20. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-976. PubMed, PubMedCentral, CrossRef
  21. Julien LA, Carriere A, Moreau J, Roux PP.  mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010;30(4):908-921. PubMed, PubMedCentral, CrossRef
  22. Rad E, Murray JT, Tee AR.Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression. Cancers (Basel). 2018;10(1):5. PubMed, PubMedCentral, CrossRef
  23. Sourris KC, Lyons JG, de Courten MP, Dougherty SL, Henstridge DC, Cooper ME, Hage M, Dart A, Kingwell BA, Forbes JM, de Courten B. c-Jun NH2-terminal kinase activity in subcutaneous adipose tissue but not nuclear factor-kappaB activity in peripheral blood mononuclear cells is an independent determinant of insulin resistance in healthy individuals. Diabetes. 2009;58(6):1259-1265. PubMed, PubMedCentral, CrossRef
Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.