Wang Wei-Zhang, Lin Xiang-Hua, Pu Qiao-Hong, Liu Man-Yu, Li Li, Wu Li-Rong, Wu Qing-Qing, Mao Jian-Wen, Zhu Jia-Yong, Jin Xiao-Bao
Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Biochem Biophys Res Commun. 2014 Nov 21;454(3):423-8. doi: 10.1016/j.bbrc.2014.10.107. Epub 2014 Oct 27.
Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cells are insensitive to BCR-ABL tyrosine kinase inhibitor imatinib, the underlying mechanisms remain largely unknown. Here, we showed that imatinib treatment induced significant upregulation of miR-21 and downregulation of PTEN in Ph+ ALL cell line Sup-b15. Transient inhibition of miR-21 resulted in increased apoptosis, PTEN upregulation and AKT dephosphorylation, whereas ectopic overexpression of miR-21 further conferred imatinib resistance. Furthermore, knockdown of PTEN protected the cells from imatinib-induced apoptosis achieved by inhibition of miR-21. Additionally, PI3K inhibitors also notably enhanced the effects of imatinib on Sup-b15 cells and primary Ph+ ALL cells similar to miR-21 inhibitor. Therefore, miR-21 contributes to imatinib resistance in Ph+ ALL cells and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to imatinib therapy.
费城染色体阳性（Ph+）急性淋巴细胞白血病（ALL）细胞对BCR-ABL酪氨酸激酶抑制剂伊马替尼不敏感，其潜在机制仍 largely unknown。在这里，我们表明伊马替尼治疗在Ph+ ALL细胞系Sup-b15中诱导了miR-21的显著上调和PTEN的下调。瞬时抑制miR-21导致细胞凋亡增加、PTEN上调和AKT去磷酸化，而miR-21的异位过表达进一步赋予了伊马替尼抗性。此外，PTEN的敲低保护细胞免受通过抑制miR-21实现的伊马替尼诱导的凋亡。此外，PI3K抑制剂也显著增强了伊马替尼对Sup-b15细胞和原发性Ph+ ALL细胞的作用，类似于miR-21抑制剂。因此，miR-21促成了Ph+ ALL细胞中的伊马替尼抗性，拮抗miR-21通过使恶性肿瘤对伊马替尼治疗敏感而显示出治疗潜力。
