Abstract
The oncogenic and tumor-suppressive roles of AMPK in chronic myeloid leukemia (CML) are controvertible. This study aimed to investigate the cytotoxic effects of the AMPK inhibitor Compound C in the CML cell lines K562, KU812, and MEG-01. Compared to K562 cells, KU812 and MEG-01 cells were more sensitive to Compound C-mediated cytotoxicity. Moreover, Compound C induced SIRT3 upregulation in K562 cells but not in KU812 or MEG-01 cells. SIRT3 silencing increased the sensitivity of K562 cells to Compound C. Additionally; Compound C-induced autophagy attenuated its induced apoptosis in KU812 and MEG-01 cells. Compound C-induced ROS-mediated AMPKα inactivation resulted in the downregulation of apoptotic regulator MCL1 in KU812 and MEG-01 cells. Mechanistically, AMPK inhibition activated p38 MAPK-mediated miR-22 expression, which in turn inhibited HuR expression, thereby reducing MCL1 mRNA stability. Overexpression of constitutively active AMPKα1 and abolishment of the activation of p38 MAPK inhibited Compound C-induced cell death and MCL1 downregulation. Furthermore, Compound C synergistically enhanced the cytotoxicity of BCR-ABL inhibitors and the BCL2 inhibitor ABT-199. Collectively, this study indicates that Compound C induces MCL1 downregulation through the AMPK/p38 MAPK/miR-22/HuR pathway, thereby inducing apoptosis of KU812 and MEG-01 cells. Furthermore, our findings suggest that AMPK inhibition is a promising strategy for improving CML therapy.