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microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2018-06-08 , DOI: 10.1016/j.cbi.2018.06.006
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

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.



中文翻译:

microRNA-199a / b-5p通过抑制WNT2信号传导介导的保护性自噬在耐伊马替尼的慢性粒细胞白血病细胞中增强伊马替尼的疗效

伊马替尼(IM)是治疗血液疾病的慢性粒细胞白血病(CML)的一线治疗药物。BCR-ABL结构域中的突变会增加CML中IM抗性的形成。但是,并非所有患者都依赖BCR-ABL结构域突变。在获得性IM抗性的发展过程中研究非突变机制是一个关键问题。我们探讨了在CML中影响IM疗效和耐药性的机制。在耐IM的K562(K562R)细胞中发现了更高的保护性自噬。抑制剂氯喹和3-甲基腺嘌呤对自噬的抑制作用增强了IM在K562R细胞中的效力。此外,与亲本细胞相比,K562R细胞中的microRNA(miR)-199a / b-5p被下调。miR-199a / b-5p的过表达减少自噬并诱导细胞凋亡,从而导致IM在K562R细胞中的效力增强。此外,在K562R细胞中,自噬的正向调节剂Wingless型MMTV整合位点家族成员2(WNT2)的表达水平明显更高,并且已被证实是miR-199a / b-5p的直接靶基因。miR-199a / b-5p的过表达抑制WNT2下游信号传导。此外,WNT2的过表达和敲低影响自噬形成和CML对IM的敏感性。WNT2的过表达还可以逆转K562R细胞中miR-199a / b-5p增强的IM功效。这些结果强调了miR-199a / b-5p通过抑制WNT2信号传导抑制自噬,并可能为未来的IM抗CML治疗和药物开发提供新的治疗策略。其在K562R细胞中的表达明显更高,并且已被证实是miR-199a / b-5p的直接靶基因。miR-199a / b-5p的过表达抑制WNT2下游信号传导。此外,WNT2的过表达和敲低影响自噬形成和CML对IM的敏感性。WNT2的过表达还可以逆转K562R细胞中miR-199a / b-5p增强的IM功效。这些结果强调了miR-199a / b-5p通过抑制WNT2信号传导抑制自噬,并可能为未来的IM抗CML治疗和药物开发提供新的治疗策略。其在K562R细胞中的表达明显更高,并且已被证实是miR-199a / b-5p的直接靶基因。miR-199a / b-5p的过表达抑制WNT2下游信号传导。此外,WNT2的过表达和敲低影响自噬形成和CML对IM的敏感性。WNT2的过表达还可以逆转K562R细胞中miR-199a / b-5p增强的IM功效。这些结果强调,miR-199a / b-5p通过抑制WNT2信号传导抑制自噬,并可能为未来的耐IM的CML治疗和药物开发提供新的治疗策略。WNT2的过表达还可以逆转K562R细胞中miR-199a / b-5p增强的IM功效。这些结果强调了miR-199a / b-5p通过抑制WNT2信号传导抑制自噬,并可能为未来的IM抗CML治疗和药物开发提供新的治疗策略。WNT2的过表达还可以逆转K562R细胞中miR-199a / b-5p增强的IM功效。这些结果强调了miR-199a / b-5p通过抑制WNT2信号传导抑制自噬,并可能为未来的IM抗CML治疗和药物开发提供新的治疗策略。

更新日期:2018-06-08
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