miR-134 increases the antitumor effects of cytarabine by targeting Mnks in acute myeloid leukemia cells

Kankan Chen, Yue Chen, Zhi Chen, Yuye Shi, Zhengmei He, Banghe Ding, Chunling Wang, Liang Yu Department of Hematology, the Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu, China Abstract: The relapse and resistance to cytarabine (Ara-C) therapy is still a dominating obstacle to the successful clinical treatment of acute myeloid leukemia (AML). Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to anticancer drugs; yet, the mechanism is not fully understood. In this study, we showed a significant downregulation of miR-134 in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-134 sensitized K562/A02 and HL-60/ADM cells to Ara-C, inhibited cell colony formation, and enhanced the ability of Ara-C to induce apoptosis. Mechanistic analyses revealed that Mnks was a putative target of miR-134, which was inversely correlated with miR-134 expression in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Further investigation showed that miR-134 increased the antitumor effects of Ara-C through inhibiting phosphorylation of eukaryotic initiation factor 4E and downregulating Mcl-1 and bcl2, which was independent of p38 and Erk1/2 activation. Taken together, our results demonstrate that miR-134 plays a pivotal role in AML Ara-C resistance through increasing cell sensitivity to Ara-C and promoting apoptosis by targeting Mnks. Keywords: miR-134, acute myeloid leukemia, Mnks, eIF4E, apoptosis