title: Radioresistant cancer cells can be conditioned to enter senescence by mTOR inhibition.
abstract: 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 by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Otolaryngology, and Biomedical Research Center, Asan Medical Center, University of Ulsan, Ulsan, Korea.
authors.forename: Hae Yun
authors.initials: HY
authors.lastname: Nam
authors.forename: Myung Woul
authors.initials: MW
authors.lastname: Han
authors.forename: Hyo Won
authors.initials: HW
authors.lastname: Chang
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Myungjin
authors.initials: M
authors.lastname: Lee
authors.forename: Hyang Ju
authors.initials: HJ
authors.lastname: Lee
authors.forename: Byoung Wook
authors.initials: BW
authors.lastname: Lee
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Min Kyo
authors.initials: MK
authors.lastname: Jung
authors.forename: Hyesung
authors.initials: H
authors.lastname: Jeon
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Neung Hwa
authors.initials: NH
authors.lastname: Park
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019073:HT29 Cells; D006570:Heterochromatin / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D010307:Parotid Neoplasms / Q000378:metabolism / Q000473:pathology; D011687:Purines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D006570:Heterochromatin; D007211:Indoles; D011687:Purines; D058570:TOR Serine-Threonine Kinases; D001616:beta-Galactosidase; C572919:PP242; D020123:Sirolimus