Overexpression of Insulin Receptor Substrate 1 (IRS1) Promotes Radioresistance in A172 Glioblastoma Cell Line

Abstract

Insulin receptor substrate 1 (IRS1) is the main adaptor molecule in insulin and insulin like growth factor signaling. Increased level of expression of IRS1 and IGF-1R proteins are associated with many human malignancies. They also induced resistance to therapeutic approaches such as chemo-and radiotherapy in cancer treatment however their molecular mechanisms are still unclear. Glioblastoma Multiforme (GBM) is the most common primary brain tumor in adults and radiotherapy has a pivotal role in its treatment. In this study, it is aimed to determine the relationship between IRS1 expression and radiosensitivity of GBM cells. Therefore, A172 cells transfected with pcDNA3.1-HA-tagged human IRS1 gene. Its overexpression was confirmed by western blot. IRS1 overexpressed A172 cells were irradiated with 5,8 and 10 Gray ionizing radiation and their effects on cell viability determined by MTT and clonogenic assay. Our results showed that overexpression of IRS1 led a decrease on sensitivity of the radiation in GBM cel ls. As a conclusion, this study should be confirmed by further molecular analysis and in vivo studies. IRS1 may be a predictive marker of radiosensitivity for GBM.

Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle–Apoptosis and PI3K Signalling Pathways

“…MS13 treatment on DU 145 and PC-3 cells also led to the downregulation of several mutually regulated DEGs associated with PI3K pathway, including IRS1, ITGA3, ITGA6, and LAMA3. IRS1 is the principal effector of the insulin and insulin-like growth factor signalling pathways, by which its expression often linked to tumorigenesis and radioresistance (White et al, 1985;Gorgisen et al, 2019). Upregulation of IRS1 increases tumour proliferation and metastasis in many human malignancies, including PCa and breast cancer cells (Chang et al, 2002;Byron et al, 2006;Reiss et al, 2012).…”

Inhibiting insulin and mTOR signaling by afatinib and crizotinib combination fosters broad cytotoxic effects in cutaneous malignant melanoma

“…Increasing evidence suggests that mTOR is able to phosphorylate several residues of IRS proteins in the insulin signaling pathway which affect their signaling 40 . IRS-1 has been shown to play a pivotal role in cancer cell proliferation and BRAFi therapy resistance and upregulation is observed in many malignancies 18 , 41 . Here we have shown that concomitant silencing of RPS6 and IRS-1 was able to further potentiate apoptotic cell death in CMM cells and cause a loss in cellular proliferation.…”