title: 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.
authors.affiliation: Division of Hematology, Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, People's Republic of China. yyaner8645@sina.com
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.forename: S
authors.initials: S
authors.lastname: Zhu
authors.forename: R
authors.initials: R
authors.lastname: Kang
authors.forename: P
authors.initials: P
authors.lastname: Vernon
authors.forename: D
authors.initials: D
authors.lastname: Tang
authors.forename: L
authors.initials: L
authors.lastname: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D001549:Benzamides; C546086:MIRN30b microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate