Knockdown of c-Myc activates Fas-mediated apoptosis and sensitizes A549 cells to radiation

Several studies have demonstrated that cancer radiosensitivity is associated with the deregulation of c-Myc, but the relationship between c-Myc and Fas in radioresistance of lung adenocarcinoma remains unclear. In this study, we established radiation-resistant A549 cell model (A549/R), and investigated the roles of c-Myc and Fas in radiation-induced cytotoxicity of A549 cells. Apoptosis detection showed that there were fewer apoptotic cells in A549/R cells treated with radiation than in A549 cells. Western blotting results demonstrated the inverse expression pattern of c-Myc and Fas in A549 and A549/R cells. Suppression of c-Myc expression by small interfering RNA (siRNA) displayed enhancement of Fas-mediated apoptosis in A549/R cells, accompanying a significant decrease of Bid, Bcl-2, pro-caspase-8, -9 and -3 and increase of Bax. In contrast, Fas-mediated apoptosis was attenuated while Fas expression was suppressed by ectopic expression of c-Myc in A549 cells. Moreover, decreased cell viability and increased induction of apoptosis were observed in A549/R cells followed by combinational treatment of c-Myc siRNA and irradiation, whereas, upregulation of c-Myc reduced the sensitivity of A549 cells to irradiation. These results indicated that c-Myc and Fas regulated the sensitivity of A549 cells to irradiation by regulating caspase-8-mediated Bid activation and the subsequent association with the mitochondrial pathway of apoptosis.