The Insulin Receptor Substrate 2 Mediates the Action of Insulin on HeLa Cell Migration via the PI3K/Akt Signaling Pathway

Abstract

Insulin signaling plays an important role in the development and progression of cancer since it is involved in proliferation and migration processes. It has been shown that the A isoform of the insulin receptor (IR-A) is often overexpressed, and its stimulation induces changes in the expression of the insulin receptor substrates (IRS-1 and IRS-2), which are expressed differently in the different types of cancer. We study the participation of the insulin substrates IRS-1 and IRS-2 in the insulin signaling pathway in response to insulin and their involvement in the proliferation and migration of the cervical cancer cell line. Our results showed that under basal conditions, the IR-A isoform was predominantly expressed. Stimulation of HeLa cells with 50 nM insulin led to the phosphorylation of IR-A, showing a statistically significant increase at 30 min (p ≤ 0.05). Stimulation of HeLa cells with insulin induces PI3K and AKT phosphorylation through the activation of IRS2, but not IRS1. While PI3K reached the highest level at 30 min after treatment (p ≤ 0.05), AKT had the highest levels from 15 min (p ≤ 0.05) and remained constant for 6 h. ERK1 and ERK2 expression was also observed, but only ERK2 was phosphorylated in a time-dependent manner, reaching a maximum peak 5 min after insulin stimulation. Although no effect on cell proliferation was observed, insulin stimulation of HeLa cells markedly promoted cell migration.

ULK2 suppresses ovarian cancer cell migration and invasion by elevating IGFBP3

“…Previous studies have identified a minimum of seven insulin-like IGFBPs that have the capability to bind to insulin-like growth factor I (IGF-I) and IGF-II, thereby regulating their activity and signaling functionality ( Izutsu et al, 2022 ; Alterki et al, 2021 ; Hjortebjerg et al, 2021 ; Agerholm et al, 2020 ). IGFBPs and IGF play pivotal roles in the IGF signaling pathway, exerting significant impacts on tumor initiation, progression, metastasis, and chemoresistance ( Han & Kim, 2021 ; Lee, Tocheny & Shaw, 2022 ; Lee et al, 2022 ; Du et al, 2017 ; Martinez Baez et al, 2023 ) that lead to antitumor effects ( Cai, Dozmorov & Oh, 2020 ). For example, Kuhn et al (2023) discovered that IGFBP3 inhibited lung cancer cell invasion and proliferation and was linked to the patients’ enhanced survival.…”

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

“…1a) (Supplementary information 1). Alterations in epidermal growth factor receptor (EGFR) [36,37], fibroblast growth factor receptor (FGFR) [38,39], platelet-derived growth factor receptor (PDGFR) [40,41], vascular endothelial growth factor receptor (VEGFR) [42,43], hepatocyte growth factor (HGF) [44,45], leukocyte receptor tyrosine kinase (LTK) [46,47], and insulin receptor (INSR) [48,49] family genes make a significant contribution to treatment failure mainly through the activation of PAM pathway (Fig. 1b) (Supplementary information 1).…”

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…IRS-1 interacts with the catalytic p110 subunit, leading to increased PIP3 and p85 regulatory subunit sequestration, which is associated with increased insulin resistance and can explain the side effects of PIK3CA inhibitors, such as hyperglycemia. IRS-1 stimulation increases GLUT-1 receptor expression and downregulates GLUT4 membrane translocation [248][249][250][251].…”