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Molecular Targets for Therapy

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

Leukemia volume 26, pages 1752–1760 (2012)Cite this article

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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.

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Acknowledgements

This work was supported by grants from The National Natural Sciences Foundation of China (30973234 and 31171328 to LC) and a grant from the University of Pittsburgh (DT).

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Authors and Affiliations

  1. Division of Hematology, Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, People's Republic of China

    Y Yu, L Yang, M Zhao, R Kang & L Cao

  2. Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China

    S Zhu

  3. Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    R Kang, P Vernon & D Tang

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  1. Y Yu
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  3. M Zhao
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Correspondence to Y Yu, D Tang or L Cao.

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Yu, Y., Yang, L., Zhao, M. et al. Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells. Leukemia 26, 1752–1760 (2012). https://doi.org/10.1038/leu.2012.65

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