Influence of pathogenetic factors of type 2 diabetes on activation of PI3K/AkT/mTOR pathway and on the development of endometrial and breast cancer

T S Vatseba

doi:10.15421/021945

Abstract

Type 2 diabetes (T2D), which is an epidemic of the 20th century, increases mortality, caused not only by cardiovascular diseases but also cancer. Pathogenetic factors of T2D lead to dysfunction of intracellular regulatory systems, particularly of PI3K/Akt/mTOR signaling pathway, which is involved in development of breast and endometrial cancer. During the study, the activation of this pathway by cancer and T2D was examined by determining the content of phosphorylated PRAS40 and p70S6K1. We studied the link between these kinases and pathogenetic factors of T2D. 65 women were examined. Patients were divided into four groups: І – healthy, ІІ – women with T2D, ІІІ – women with cancer without diabetes, IV – women with cancer and T2D. Level of HbA1c was determined by the ion-exchange chromatography. Levels of insulin, IGF-1, phospho-PRAS40, phospho-p70S6K1 were determined in PBMCs by immune-enzymatic methods. According to research results, significant hyperinsulinemia was detected in both groups with T2D. The highest level of insulin was in group II. A significantly higher level of IGF-1 was found only in patients with cancer of group III. The content of phospho-PRAS40 and phospho-p70S6K1 was higher in women with T2D of group II and in women with cancer of group III. Patients in group IV with combination of cancer and T2D had a lower level of phospho-PRAS40 in comparison to other groups. Phospho-PRAS40 in group II correlates with insulin, IGF-1 and HbA1c; in groups III and IV only with BMI. Phospho-p70S6K1 correlates with IGF-1 and with HbA1c in group II. Pathogenetic factors of T2D activate the signal path PI3K/Akt/mTOR, which is involved in the regulation of oncogenesis and metabolism. Phosphorylation of PRAS40 and p70S6K1 reflects the activation of P13K/Akt/mTOR pathway in women with T2D. Increased levels the phospho-PRAS40 and phospho-p70S6K1 can be used as early markers of oncogenesis in women with T2D.

Highlights

Patients with Type 2 diabetes (T2D) have an increased risk of certain localized cancers, including breast, endometrial (Joung et al, 2015), pancreas (Beg et al, 2014), prostate (Gang et al, 2015), liver and intestine cancer (Harding et al, 2015; Zhu et al, 2017; Vatseba & Sokolova, 2018)
It has been found that breast and endometrial cancer occur in postmenopausal women with T2D on the background of obesity
S6 kinase; RAS – membrane-bound proteins, which are involved in signal transduction; RAF – proteins, components of mytogen-activated protein kinase (MAPK) kinase; MAPK – mitogen-activated protein kinase; ROS –reactive oxygen species; LKB1 – liver kinase B1; AMPK – adenosine monophosphateactivated protein kinase; TSC2 – tuberous sclerosis complex 2; – stimulation; – inhibition ; – regulation

Summary

Introduction

Patients with T2D have an increased risk of certain localized cancers, including breast, endometrial (Joung et al, 2015), pancreas (Beg et al, 2014), prostate (Gang et al, 2015), liver and intestine cancer (Harding et al, 2015; Zhu et al, 2017; Vatseba & Sokolova, 2018). A scientific discussion about cancer as a possible consequence of DM or DM as a paraneoplastic syndrome is being conducted. Breast and endometrial cancer are some of the most common types of cancer in women in the postmenopausal period (Lykholat et al, 2016). Among the mechanisms of the association of this cancer and T2D are the effects of hyperinsulinemia, obesity, cytokine imbalance and hyperglycemia (García-Jiménez et al, 2015; Hendriks et al, 2018)

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