Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

Abstract

A major advancement in the treatment of chronic myeloid leukemia (CML) has been the development of imatinib and other BCR-ABL tyrosine kinase inhibitors. MicroRNAs (miRNAs) are small RNA molecules that influence gene expression by post-transcriptional regulation of messenger RNA. It is not yet clear how miRNAs are able to regulate the effectiveness of imatinib in CML. Here, we show that imatinib markedly inhibits expression of miR-30a in human CML cells. miR-30a is a potent inhibitor of autophagy by downregulating Beclin 1 and ATG5 expression. miR-30a mimic or knockdown of autophagy genes (ATGs) such as Beclin 1 and ATG5 by short hairpin RNA enhances imatinib-induced cytotoxicity and promotes mitochondria-dependent intrinsic apoptosis. In contrast, knockdown of miR-30a by antagomir-30a increases the expression of Beclin 1 and ATG5, and inhibits imatinib-induced cytotoxicity. These findings indicate that dysregulation of miR-30a may interfere with the effectiveness of imatinib-mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target in CML.

Alteration in Autophagic-lysosomal Potential During Aging and Neurological Diseases: The microRNA Perspective

“…miR-30a was reported to control rapamycin-induced autophagy by targeting beclin 1 [61 • ]. Further studies confirmed the role of miR-30a in autophagy regulation [62][63][64][65]. Zou et al [62] showed that miR-30a blocked cisplatin-induced autophagy and sensitized tumor cells to death.…”

“…Zou et al [62] showed that miR-30a blocked cisplatin-induced autophagy and sensitized tumor cells to death. Again, miR-30a augmented imatinib treatment efficacy in chronic myeloid leukemia, and Atg5 and beclin 1 level changes caused by the miRNA contributed to the observed effect [63]. Additionally, two other studies provided evidence about the importance of miR-30a in autophagy of cardiomyocytes [64,65].…”

Application and interpretation of current autophagy inhibitors and activators

“…Recently, miR-30a has been shown to be a potent autophagic inhibitor by downregulating Beclin 1 and ATG5 expression. In contrast, knockdown of miR-30a by antagomir-30a increases the expression of Beclin 1 and ATG5 [111] . Although previous reports have shown that downregulation of ATG7, ATG5, or BECN1 by RNAi significantly decreases autophagy, it should be noted that autophagy may also occur in the absence of some of these key autophagic proteins.…”

Role of autophagy in the maintenance and function of cancer stem cells

“…This finding supports the use of DCLK1 as a potential target to sensitize tumors to curcumin. Finally, the depletion of autophagy by different approaches increased the cytotoxicity of the tyrosine kinase inhibitor imatinib or the AKT inhibitor perifosine (two drugs reported to activate autophagy) in CML cell lines (Bellodi et al, 2009, Elzinga et al, 2013, Rothe et al, 2014, Tong et al, 2012, Yu et al, 2012. On the other hand, the cytotoxic effect of some therapeutic agents is mediated by (and strictly requires) the molecular machinery of autophagy.…”