microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells

Peng Hsu Chen, Ann Jeng Liu, Kuo Hao Ho, Ya Ting Chiu, Zhe Harn Anne Lin, Yi Ting Lee, Chwen Ming Shih, Ku Chung Chen

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Imatinib (IM) is a first-line therapeutic drug for chronic myeloid leukemia (CML), a hematological disease. Mutations in the BCR-ABL domain increase formation of IM resistance in CML. However, not all patients are BCR-ABL domain-mutant dependent. Investigating non-mutant mechanisms in the development of acquired IM resistance is a critical issue. We explored the mechanisms which influence IM efficacy and resistance in CML. Higher protective autophagy was identified in IM-resistant K562 (K562R) cells. Inhibition of autophagy by the inhibitors, chloroquine and 3-methyladenine, enhanced IM's efficacy in K562R cells. In addition, microRNA (miR)-199a/b-5p were downregulated in K562R cells compared to parent cells. Overexpression of miR-199a/b-5p reduced autophagy and induced cell apoptosis, resulting in enhanced IM's efficacy in K562R cells. Moreover, expression levels of the Wingless-type MMTV integration site family member 2 (WNT2), a positive regulator of autophagy, were significantly higher in K562R cells, and it was validated as a direct target gene of miR-199a/b-5p. Overexpressions of miR-199a/b-5p inhibited WNT2 downstream signaling. Furthermore, overexpression and knockdown of WNT2 influenced autophagy formation and CML drug sensitivity to IM. Overexpression of WNT2 could also reverse miR-199a/b-5p-enhanced IM efficacy in K562R cells. These results emphasized that miR-199a/b-5p inhibited autophagy via repressing WNT2 signaling and might provide novel therapeutic strategies for future IM-resistant CML therapy and drug development.

Original languageEnglish
Pages (from-to)144-151
Number of pages8
JournalChemico-Biological Interactions
Volume291
DOIs
Publication statusPublished - Aug 1 2018

Keywords

  • Autophagy
  • Chronic myeloid leukemia (CML)
  • Imatinib resistance
  • miR-199a-5p
  • miR-199b-5p
  • WNT2

ASJC Scopus subject areas

  • Toxicology

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