Inhibition of ERK5 enhances cytarabine-induced apoptosis in acute myeloid leukemia cells

Background and aims: Acute myeloid leukemia (AML) is a fatal hematological malignancy which is resistant to a variety of chemotherapy drugs. Phospho-ERK5 (p-ERK5) plays a novel role in chemoresistance in some cancer cells and this pathway is a central mediator of cell survival and apoptotic regulation. The aim of this study was to investigate the effect of a specific ERK5 small interference RNA (siRNA) on proliferation and the sensitivity of HL-60 acute myeloid leukemia (AML) cells to the chemotherapeutic drug cytarabine. Methods: The cells were transfected with siRNAs using Lipofectamine T 2000 transfection reagent. Relative ERK5 mRNA and protein levels were measured by quantitative real-time PCR, immunocytochemical assay, and Western blotting, respectively. The cytotoxic effects of cytarabine and ERK5 siRNA, alone and in combination, on leukemic cells were determined using colony formation and MTT assay. Apoptosis was assessed by ELISA cell death assay. Results: ERK5 siRNA markedly reduced both mRNA and protein expression levels leading to distinct inhibition of cell proliferation and increased spontaneous apoptosis. Surprisingly, ERK5 siRNA synergistically increased the cell toxic effects of cytarabine. Conclusions: Our study suggests that down-regulation of ERK5 by siRNA can trigger apoptosis and overcome drug resistance of leukemia cells. Therefore, ERK5 siRNA may be an effective adjuvant in AML chemotherapy.