Abdelhalim Azzi

SHIP2 inhibition alters redox‐induced PI3K/AKT and MAP kinase pathways via PTEN over‐activation in cervical cancer cells

Phosphatidylinositol (3,4,5)‐trisphosphate (PI(3,4,5)P3) is required for protein kinase B (AKT) activation. The level of PI(3,4,5)P3 is constantly regulated through balanced synthesis by phosphoinositide 3‐kinase (PI3K) and degradation by phosphoinositide phosphatases phosphatase and tensin homologue (PTEN) and SH2‐domain containing phosphatidylinositol‐3,4,5‐trisphosphate 5‐phosphatase 2 (SHIP2), known as negative regulators of AKT. Here, I show that SHIP2 inhibition in cervical cancer cell lines alters H2O2‐mediated AKT and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathway activation. In addition, SHIP2 inhibition enhances reactive oxygen species generation. Interestingly, I found that SHIP2 inhibition and H2O2 treatment enhance lipid and protein phosphatase activity of PTEN. Pharmacological targeting or RNA interference(RNAi) mediated knockdown of PTEN rescues extracellular signal‐regulated kinase and AKT activation. Using a series of pharmacological and biochemical approaches, I provide evidence that crosstalk between SHIP2 and PTEN occurs upon an increase in oxidative stress to modulate the activity of mitogen‐activated protein kinase and phosphoinositide 3/ATK pathways.