Abstract
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.
Highlights
Mitochondrial transcription factor A is critical in regulating mitochondrial DNA transcription, packaging and copy number [1,2,3]
We identified that COX-2 derived prostaglandin E2 (PGE2) enhanced the activation of p38-MAPK, which further stimulated Dynamin-related protein 1 (DRP1)-mediated up-regulation of TFAM
The D10 and D0 for Hep G2 cells transfected with shTFAM1 and shTFAM2 plasmids were 4.38 Gy, 1.83 Gy, and 3.49 Gy, 1.44 Gy respectively. These results indicated that the knockdown of TFAM expression increased the sensitivity of U-2 OS and Hep G2 cells to radiation
Summary
Mitochondrial transcription factor A (mtTFA, mtTF1, TFAM) is critical in regulating mitochondrial DNA (mtDNA) transcription, packaging and copy number [1,2,3]. Preventing mitochondrial fragmentation impaired mitochondrial functions, and led to the loss of mitochondrial DNA [25], indicating that the potential association between mitochondrial morphologies and TFAM was involved in the regulation of mitochondrial biogenesis [3,26,27] Both TFAM and COX-2 contribute to the resistance of cancer cells to radiation, and they are considered as potential targets for improving the efficacy of radiation treatment in cancers. They are mitochondrial proteins, and affect mitochondrial functions. Our results provided new information on the mechanisms for how COX-2 affects mitochondrial functions, and its implications in increasing the sensitivity of cancer cells to radiation during therapy.
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