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

Chem Biol Interact. 2018 Aug 1;291:144-151. doi: 10.1016/j.cbi.2018.06.006. Epub 2018 Jun 8.

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.

Keywords: Autophagy; Chronic myeloid leukemia (CML); Imatinib resistance; WNT2; miR-199a-5p; miR-199b-5p.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Apoptosis / drug effects
  • Autophagy* / drug effects
  • Base Sequence
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Humans
  • Imatinib Mesylate / pharmacology
  • Imatinib Mesylate / therapeutic use*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • MicroRNAs / metabolism*
  • Signal Transduction* / drug effects
  • Treatment Outcome
  • Wnt2 Protein / metabolism*

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Wnt2 Protein
  • mirn199 microRNA, human
  • Imatinib Mesylate