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

FEBS Lett. 2013 Jan 4;587(1):5-16. doi: 10.1016/j.febslet.2012.11.003. Epub 2012 Nov 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Carcinoma / drug therapy
  • Carcinoma / metabolism
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Oxides / pharmacology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Shc Signaling Adaptor Proteins / antagonists & inhibitors
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism
  • Signal Transduction / drug effects*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Arsenicals
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Oxides
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • SHC1 protein, human
  • SKIL protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • Arsenic Trioxide