Repressing IRS1/2 by NT157 inhibits the malignant behaviors of ovarian cancer through inactivating PI3K/AKT/mTOR pathway and inducing autophagy

Insulin Receptor substrate 1 and 2 (IRS1/2) have been found involved in many cancers development and their inhibitors exert significant tumor-suppressive effects. Here, we tried to explore the function of NT157, an IGF1R-IRS1/2 inhibitor, in ovarian Cancer. We treated ovarian Cancer cells with varying doses of NT157. The MTT assay was employed to evaluate cell proliferation and colony formation assay was used for detecting colony-forming ability. TUNEL assay was adopted to test cell Apoptosis. Cell invasion was checked by the Transwell assay. The expression of apoptosis-related proteins, Autophagy markers, IRS1/2, and PI3K/Akt/mTOR pathway was compared by Western blot, immunofluorescence, or qRT-PCR. As indicated by the data, NT157 abated the viability, proliferation, and induced Autophagy of ovarian Cancer cells. Overexpressing IRS1/2 attenuated the tumor-suppressive effect of NT157 and heightened the PI3K/Akt/mTOR pathway activation. Inhibition of the PI3K/Akt/mTOR pathway enhanced the tumor-suppressive effect of NT157 and facilitated NT157-mediated Autophagy. However, the Autophagy Inhibitor 3-MA partly reversed NT-157-mediated antitumor effects. In conclusion, this study disclosed that NT157 suppressed the malignant phenotypes of ovarian Cancer cells by inducing Autophagy and hampering the expression of IRS1/2 and PI3K/Akt/mTOR pathway.

IRS1/2; NT157; autophagy; ovarian cancer.