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 (As2O3, used in treating APL) induces SnoN to oppose the apoptotic response in ovarian cancer cells. We now report that As2O3 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, As2O3 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 interactionsShcAphysically interacts with GRB2 by anti bait coimmunoprecipitation (View interaction)EGFRphysically interacts with ShcA by anti bait coimmunoprecipitation (View interaction)EGFRphysically interacts with GRB2 and ShcA by anti bait coimmunoprecipitation (View interaction)

► SnoN, a TGFβ regulator at 3q26.2, is dysregulated in ovarian cancer.
► Expression of SnoN/SkiL is induced with As2O3 in ovarian cancer cells.
► As2O3 activates EGFR/p66 ShcA and increases their interaction with Grb2.
► As2O3 activates Src and PI3K/AKT pathway to modulate SnoN expression and ovarian cancer cell survival.
► Pathways of As2O3-induced SnoN induction may provide targets for cancer treatment.