Downregulation of Mcl-1 through GSK-3 beta activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells

作者：Wang R; Xia L; Gabrilove J; Waxman S; Jing Y^*

来源：Leukemia, 2013, 27(2): 315-324.

DOI：10.1038/leu.2012.180

• arsenic trioxide
• Mcl-1
• glycogen synthase kinase-3 beta
• myeloid leukemia
• apoptosis

Arsenic trioxide (ATO) induces disease remission in acute promyelocytic leukemia (APL) patients, but not in non-APL acute myeloid leukemia (AML) patients. ATO at therapeutic concentrations (1-2 mu m) induces APL NB4, but not non-APL HL-60, cells to undergo apoptosis through the mitochondrial pathway. The role of antiapoptotic protein Mcl-1 in ATO-induced apoptosis was determined. The levels of Mcl-1 were decreased in NB4, but not in HL-60, cells after ATO treatment through proteasomal degradation. Both glycogen synthase kinase-3 beta (GSK-3 beta) inhibitor SB216763 and siRNA blocked ATO-induced Mcl-1 reduction as well as attenuated ATO-induced apoptosis in NB4 cells. Silencing Mcl-1 sensitized HL-60 cells to ATO-induced apoptosis. Both ERK and AKT inhibitors decreased Mcl-1 levels and enhanced ATO-induced apoptosis in HL-60 cells. Sorafenib, an Raf inhibitor, activated GSK-3 beta by inhibiting its phosphorylation, decreased Mcl-1 levels and decreased intracellular glutathione levels in HL-60 cells. Sorafenib plus ATO augmented reactive oxygen species production and apoptosis induction in HL-60 cells and in primary AML cells. These results indicate that ATO induces Mcl-1 degradation through activation of GSK-3 beta in APL cells and provide a rationale for utilizing ATO in combination with sorafenib for the treatment of non-APL AML patients. Leukemia (2013) 27, 315-324; doi:10.1038/leu.2012.180

• 出版日期2013-2