Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation

Cancer Lett. 2009 Nov 1;284(2):208-15. doi: 10.1016/j.canlet.2009.04.035. Epub 2009 May 19.


Arsenic trioxide (ATO) strongly induces apoptosis in acute promyelocytic leukemia (APL), but it induces cell cycle arrest in most solid tumors. In this study, we investigated the mechanism of ATO action on APL-derived NB4 cells and gastric cancer cell lines. ATO decreased the viability of both cell lines, but gastric cancer cells were much less susceptible. ATO-induced G2/M phase arrest and p53 degradation in gastric cancer MGC803 cells. In contrast, ATO-induced apoptosis in NB4 cells without degradation of p53. Both processes were accompanied by transient activation of Akt. The PI3K/Akt inhibitor LY294002 significantly increased the amount of p53 protein and ATO-induced apoptosis in both cell lines and decreased G2/M phase arrest of MGC803 cells. In addition, ATO up-regulated the expression of Cbl proteins in both cell lines. Inhibition of Cbl with the proteasome inhibitor Ps341 decreased apoptosis in NB4 cells and increased the G2/M phase arrest of MGC803 cells, and it also prolonged the activation of PI3K/Akt by ATO. Consistent results with those in MGC803 cells were showed in gastric cancer cell BGC823 and SGC7901 after ATO treatment. These results demonstrate that inhibition of PI3K/Akt signaling by Cbl is involved in both ATO-induced apoptosis of NB4 cells and ATO-induced G2/M phase arrest of gastric cancer cells. Cbl achieved these effects probably via its regulating PI3K/Akt pathway, and thereby modulated p53 activation.

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • G2 Phase / drug effects*
  • G2 Phase / physiology
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Leukemia, Promyelocytic, Acute / metabolism
  • Leukemia, Promyelocytic, Acute / pathology
  • Metaphase / drug effects*
  • Metaphase / physiology
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / physiology
  • Oxides / pharmacology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins c-cbl / drug effects*
  • Proto-Oncogene Proteins c-cbl / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Tumor Suppressor Protein p53 / physiology*
  • Ubiquitination / drug effects
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • Arsenicals
  • Neoplasm Proteins
  • Oxides
  • Phosphoinositide-3 Kinase Inhibitors
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-cbl
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • CBL protein, human
  • Arsenic Trioxide