Nam, Hae Yun Han, Myung Woul Chang, Hyo Won Lee, Yoon Sun Lee, Myungjin Lee, Hyang Ju Lee, Byoung Wook Lee, Hee Jin Lee, Kyung Eun Jung, Min Kyo Jeon, Hyesung Choi, Seung-Ho Park, Neung Hwa Kim, Sang Yoon Kim, Seong Who 2024-01-20T12:01:59Z 2024-01-20T12:01:59Z 2021-09-05 2013-07-15 0008-5472 https://pubs.kist.re.kr/handle/201004/127871 Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated beta-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated beta-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity. (C) 2013 AACR. English AMER ASSOC CANCER RESEARCH INDUCED PREMATURE SENESCENCE TUMOR-CELLS DNA-DAMAGE AUTOPHAGY PATHWAY RAPAMYCIN CYCLE RADIATION HEAD RB Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition Article 10.1158/0008-5472.CAN-12-3516 1 CANCER RESEARCH, v.73, no.14, pp.4267 - 4277 CANCER RESEARCH 73 14 4267 4277 scie scopus 000321823600011 Oncology Oncology Article INDUCED PREMATURE SENESCENCE TUMOR-CELLS DNA-DAMAGE AUTOPHAGY PATHWAY RAPAMYCIN CYCLE RADIATION HEAD RB