Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide

Dennis J. Goussetis, Jessica K. Altman, Heather Glaser, Jennifer L. McNeer, Martin S. Tallman, Leonidas C. Platanias

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

Arsenic trioxide (As2O3) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As 2O3 is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As2O3 appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As2O3 on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As2O3 on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As2O3 and possibly other heavy metal derivatives.

Original languageEnglish (US)
Pages (from-to)29989-29997
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number39
DOIs
StatePublished - Sep 24 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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