Mechanism Of COX-2 Regulating TFAM Expression And Its Effect On Radiosensitivity Of Tumor Cells

Tumor radiation therapy,is radiotherapy,has been extensively used in the clinical treatment of cancer patients.Induction of radiotherapy leads to over expression of certain proteins in tumor cells,which in turn causes radiation resistance of tumor cells.Finding targets to increase the radiation sensitivity of tumor cells and enhancing the sensitivity of lung cancer cells to radiation is of great significance for tumor therapy.Mitochondrial transcription factor A(TFAM)is a key regulator of mitochondrial biogenesis.Studies have shown that inhibition of TFAM expression increase cancer cell sensitivity to chemotherapeutic drugs or ionizing radiation,and cause apoptosis.Cyclooxygenase-2(COX-2)plays an important part in inflammation and tumorigenesis.Increased COX-2 expression is considered to be one of the hallmarks of tumor cell proliferation.Studies have shown that inhibition of COX-2 expression increases the radiation sensitivity of cancer cells,and COX-2 signaling pathway is a potential therapeutic target in cancer.To sum up,the increased expression of TFAM and COX-2 in cells will lead to the decrease of the sensitivity of tumor cells to ionizing radiation,but whether there is a regulatory relationship between them has not been reported.In this paper,the following main results were obtained by using U-2 OS and Hep G2 human tumor cells as objects and using y-rays as irradiation methods,to study the role and relationship of TFAM and COX-2 in radiation resistance of human tumor cells.The main results were as follows:1.Knockdown of TFAM expression increased the sensitivity of U-2 OS and HepG2 cells to radiation.(1)Activation of TFAM and COX-2 in ly-ray irradiated tumor cells.(2)TFAM knockdown sensitizing U-2 OS and Hep G2 to ionizing radiation.2.Activation of COX-2 upregulates TFAM in irradiated cells.(1)Selective COX-2 inhibitor NS-398 treatment blocked the induced expression of TFAM in irradiated tumor cells.(2)NS-398 increases radiation-induced tumor cell death.3.Radiation-activated p38 promotes the expression of DRPI/TFAM.(1)Mitochondrial fragmentation mediated by DRP1 up-regulates TFAM in irradiated cells.(2)The DRP1 siRNA and selective chemical inhibitor Mdivi-1 decreased the radiation induced TEAM expression.4.Radiation induced COX-2 activated p38 and promoted the expression of DRP1/TFAM.(1)Selective COX-2 inhibitor NS-398 treatment blocked the induced expression of P-p38 and DRP1 in irradiated tumor cells.(2)COX-2/PGE2 promotes p38 phosphorylation and DRP1 up-regulation.In conclusion,our current work provided evidence to show that COX-2 and TFAM are candidate targets for improving the efficacy of radiotherapy;COX-2 affects the expression of TFAM in tumor cells via p38-mediated DRP1-induced mitochondrial fragmentation,enhancing radiosensitivity of tumor cells.This study may provide some data and possible new research points for the radiosensitivity of tumor cells,and points out a possible clue to improve the efficacy of radiotherapy for tumor cells.