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Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells

by Fan Tang 1,2,†, Rui Zhang 1,2,† and Jun Wang 1,*
Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, No. 350 of Shushanhu Road, Hefei 230031, China
School of Graduate Students, University of Science and Technology of China, Hefei 230026, China
Author to whom correspondence should be addressed.
These authors contributed equally.
Int. J. Mol. Sci. 2019, 20(5), 1218;
Received: 25 January 2019 / Revised: 22 February 2019 / Accepted: 7 March 2019 / Published: 11 March 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, and it is a candidate target for sensitizing tumor during therapy. Previous studies identified that increased TFAM expression conferred tumor cells resistance to ionizing radiation. However, the mechanisms on how TFAM are regulated in irradiated tumor cells remain to be explored. In this research, we demonstrated the contribution of cyclooxygenase-2 (COX-2) to enhancing TFAM expression in irradiated tumor cells. Our results showed TFAM was concomitantly up-regulated with COX-2 in irradiated tumor cells. Inhibition of COX-2 by NS-398 blocked radiation-induced expression of TFAM, and prostaglandin E2 (PGE2) treatment stimulated TFAM expression. We next provided evidence that DRP1-mediated mitochondrial fragmentation was a reason for TFAM up-regulation in irradiated cells, by using small interfering RNA (siRNA) and selective inhibitor-targeted DRP1. Furthermore, we proved that p38-MAPK-connected COX-2, and DRP1-mediated TFAM up-regulation. Enhanced phosphorylation of p38 in irradiated tumor cells promoted DRP1 expression, mitochondrial fragmentation, and TFAM expression. NS-398 treatment inhibited radiation-induced p38 phosphorylation, while PGE2 stimulated the activation of p38. The results put forward a mechanism where COX-2 stimulates TFAM expression via p38-mediated DRP1/mitochondrial fragmentation signaling in irradiated tumor cells, which may be of value in understanding how to sensitize cancer cells during radiotherapy. View Full-Text
Keywords: radio-sensitivity; TFAM; COX-2; mitochondrial fragmentation; p38-MAPK radio-sensitivity; TFAM; COX-2; mitochondrial fragmentation; p38-MAPK
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Tang, F.; Zhang, R.; Wang, J. Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells. Int. J. Mol. Sci. 2019, 20, 1218.

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