MicroRNAs Contribute to Promyelocyte Apoptosis in As2O3-Treated APL Cells

Abstract

Background: Arsenic trioxide (As₂O₃), an ancient drug used in traditional Chinese medicine, has substantial anticancer activities, especially in the treatment of patients suffering from acute promyelocytic leukemia (APL); however the underlying mechanisms are not well understood. Methods: MTT assay was used to detect the cell viability. Flow Cytometry analysis and caspase-3 activity assay were used to measure apoptosis of APL cells. Caspase-3 and Bax levels were analyzed by western blot and let-7d and miR-766 levels were determined by real-time RT-PCR. Results: As₂O₃ significantly inhibited cell viability and induced apoptosis in APL cells. Several microRNAs, including let-7d and miR-766, were dysregulated in APL cells treated with As₂O₃. The expression of caspase-3 and Bax, which are targets of let-7d and miR-766, respectively, were up-regulated in As₂O₃ treated cells. Transfection of let-7d and miR-766 into NB4 cells decreased the expression of caspase-3 and Bax, respectively. Correspondingly, transfection of these microRNAs increased NB4 cell viability. As₂O₃ induced degradation of promyelocytic leukemia (PML), and then induced the down-regulation of both let-7d and miR-766 in NB4 cells. Conclusions: We construct a dysregulated microRNA network involved in As₂O₃-induced apoptosis in APL. Targeting this network may be a new strategy for the prevention of side effects associated with APL treatment with As₂O₃.