Abstract
SnoN/SkiL (TGFβ regulator) is dysregulated in ovarian cancer, a disease associated with acquired drug-resistance. Arsenic trioxide (As&sub2;O&sub3;, used in treating APL) induces SnoN to oppose the apoptotic response in ovarian cancer cells. We now report that As&sub2;O&sub3; increases phosphorylation of EGFR/p66ShcA and EGFR degradation. As&sub2;O&sub3; 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, As&sub2;O&sub3;-induced cleaved PARP was reduced together with increased XIAP. Collectively, As&sub2;O&sub3; 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.