eEF-2 Kinase-targeted miR-449b confers radiation sensitivity to cancer cells.
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The roles of microRNA in regulation of various biological processes and in modulation of therapeutic effects have been widely appreciated. In this study, we found a positive correlation between miR-449b expression and radiation sensitivity in cancer cells and in tumor specimens from patients. We showed that eEF-2 kinase, a negative regulator of global protein synthesis, is a target of miR-449b. Introducing a miR-449b mimic into cancer cells led to suppression of eEF-2 kinase expression, leading to increases of protein synthesis and depletion of cellular ATP. Further, we demonstrated that the miR-449b mimic rendered the cancer cells more sensitive to ionizing radiation both invitro (cell culture) and invivo (animal xenograft model). Moreover, the radiation sensitivity conferred by miR-449b could be blunted by cycloheximide, an inhibitor of protein synthesis, or by direct delivery of ATP liposome, supporting eEF-2 kinase as a mediator of the radio-sensitizing effects of miR-449b. These results indicate that miR-449b, which is frequently down-regulated in radio-resistant cancers, may represent a new critical determinant of radio-sensitivity.
author list (cited authors)
Ji, C., Xu, Q., Guo, L., Wang, X., Ren, Y., Zhang, H., ... Zhang, Y. i.
complete list of authors
Ji, Cheng||Xu, QiongHua||Guo, LingChuan||Wang, XiaoHui||Ren, YiJie||Zhang, HongHan||Zhu, WeiDong||Ming, ZhiJun||Yuan, YunSheng||Ren, XingCong||Song, JianXun||Cheng, Yan||Yang, JinMing||Zhang, Yi