Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells.
Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As(R)), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As(R) cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As(R) than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As(R). These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.
Lunghi
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P
Department of Clinical Sciences, Section of Hemato-Oncology, University of Parma, Parma, Italy. p.lunghi@libero.it
Tabilio
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Lo-Coco
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Pelicci
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PG
Pelicci
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Bonati
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D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010087:Oxides / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D010087:Oxides; D034741:RNA, Small Interfering; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D000077237:Arsenic Trioxide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one