eEF-2 Kinase-targeted miR-449b confers radiation sensitivity to cancer cells

Cheng Ji, Qiong Hua Xu, Ling Chuan Guo, Xiao Hui Wang, Yi Jie Ren, Hong Han Zhang, Wei Dong Zhu, Zhi Jun Ming, Yun Sheng Yuan, Xing Cong Ren, Jianxun Song, Yan Cheng, Jin Ming Yang, Yi Zhang

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Abstract

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-449 b 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-449 b. Introducing a miR-449 b 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-449 b mimic rendered the cancer cells more sensitive to ionizing radiation both in vitro (cell culture) and in vivo (animal xenograft model). Moreover, the radiation sensitivity conferred by miR-449 b 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-449 b. These results indicate that miR-449 b, which is frequently down-regulated in radio-resistant cancers, may represent a new critical determinant of radio-sensitivity.

Original languageEnglish (US)
Pages (from-to)64-74
Number of pages11
JournalCancer Letters
Volume418
DOIs
StatePublished - Apr 1 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Ji, C., Xu, Q. H., Guo, L. C., Wang, X. H., Ren, Y. J., Zhang, H. H., Zhu, W. D., Ming, Z. J., Yuan, Y. S., Ren, X. C., Song, J., Cheng, Y., Yang, J. M., & Zhang, Y. (2018). eEF-2 Kinase-targeted miR-449b confers radiation sensitivity to cancer cells. Cancer Letters, 418, 64-74. https://doi.org/10.1016/j.canlet.2018.01.014