SnoN/SkiL expression is modulated via arsenic trioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells

SnoN/SkiL (TGFβ regulator) is dysregulated in ovarian cancer, a disease associated with acquired drug-resistance. Arsenic trioxide (As 2O3, used in treating APL) induces SnoN to oppose the apoptotic response in ovarian cancer cells. We now report that As 2O3 increases phosphorylation of EGFR/p66ShcA and EGFR degradation. As2O3 activates Src(Y416) whose activity (inhibited by PP2) modulates EGFR activation, its interaction with Shc/Grb2, and p-AKT. Inhibition of PI3K reduces SnoN and cell survival. Although EGFR or MAPK1 siRNA did not alter SnoN expression, As2O3-induced cleaved PARP was reduced together with increased XIAP. Collectively, As 2O3 mediates an initial rise in pY-Src(416) to regulate the PI3K/AKT pathway which increases SnoN and cell survival; these early events may counter the cell death response associated with increased pY-EGFR/MAPK activation. Structured summary of protein interactions: ShcA physically interacts with GRB2 by anti bait coimmunoprecipitation (View interaction) EGFR physically interacts with ShcA by anti bait coimmunoprecipitation (View interaction) EGFR physically interacts with GRB2 and ShcA by anti bait coimmunoprecipitation (View interaction)