Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide.
Arsenic trioxide (As(2)O(3)) 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(2)O(3) is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As(2)O(3) 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 As(2)O(3) 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 As(2)O(3) 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 As(2)O(3) and possibly other heavy metal derivatives.
Goussetis
Dennis J
DJ
Division of Hematology/Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
Altman
Jessica K
JK
Glaser
Heather
H
McNeer
Jennifer L
JL
Tallman
Martin S
MS
Platanias
Leonidas C
LC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D020298:U937 Cells; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; C502661:Atg7 protein, mouse; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D010087:Oxides; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000077237:Arsenic Trioxide