Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition
Hae Yun NamMyung Woul HanHyo Won ChangYoon Sun LeeMyungjin LeeHyang Ju LeeByoung Wook LeeHee Jin Lee이경은Min Kyo Jung전혜성Seung-Ho ChoiNeung Hwa Park김상윤Seong Who Kim
Issue Date
Cancer research
VOL 73, NO 14, 4267-4277
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 β-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 β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy bymTORinhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity.
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