Insulin receptor substrate 1 overexpression promotes survival of glioblastoma cells through AKT1 activation

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant type of central nervous system tumours in adults. Strict regulation of glucose homeostasis has a significant role in GBM pathogenesis. Insulin receptor substrate 1 (IRS1) protein is the most important adaptor molecule involved in the regulation of glucose metabolism. It interacts with many cancer-related receptors and its overexpression is strongly associated with cell proliferation and survival. Our study was aimed to understand the role of IRS1 proteins in GBM cell viability. U-87 MG cells were transfected with pcDNA3.1-flagtagged-human IRS1 expression vector. Insulin induced phosphorylation levels of IRS1, AKT1 and ERK1/2 and Grb2 expression were examined to determine the effects of ectopic IRS1 overexpression on insulin signalling and the viability levels of U-87 MG cells were determined by MTT analysis. Overexpression of IRS1 in U-87 MG cells led to an increase in cell viability. Its overexpression also increased Grb2 expression and phosphorylation of AKT1 through elevation of IRS1 tyrosine phosphorylation in IRS1-transfected U-87 MG cells compared to control and mock transfected groups. Our study showed that increased IRS1 expression and activation may promote the cell viability via AKT1 activation. IRS1 signalling may be considered as a therapeutic target for further studies.

Insulin receptor substrate 1 may play divergent roles in human colorectal cancer development and progression

“…Another study documented that IRS-1-mediated signals lead to resistance to apoptosis induced by Transforming Growth Factor-β1 in hepatocellular carcinoma cells[ 27 ]. Also, overexpression of IRS-1 in glioblastoma cells was found to promote cell survival[ 28 ]. Moreover, a study on brown pre-adipocytes indicated that IGF-1 as well as insulin exerts antiapoptotic effect, which can be impaired by IRS-1 deletion and restored by its re-expression[ 29 ].…”

Effect of curcumin on activation and expression of IRS1, Grb2, K-Ras and Bax in STZ-induced diabetic rat brains

“…During insulin signaling, Grb2 binds to YVNI motifs of IRS1 and PI3K binds to YXXM motifs of IRS1 and activates SOS-RAS-RAF-MEK-ERK and PI3K-AKT pathways respectively [3,18]. Grb2 is one of the members of biological network proteins that are identified by Ingenuity Systems Pathway Analysis (IPA) platform in CAL27 cells after curcumin treatment [19].…”

Prognostic and Therapeutic Roles of the Insulin Growth Factor System in Glioblastoma

“…Insulin signaling is robustly activated in human glioma cells independently of insulin stimulation, since the catalytic subunit of the InsR strongly phosphorylates and recruits IRS-1 leading to the activation of AKT and ERK2 (41) (Figure 1A). Furthermore, experiments conducted in insulin-stimulated IRS-1-transfected glioma cell showed high phosphorylation levels of AKT, ERK1/2 and overexpression of Grb2 resulting in increased cell viability (42).…”