title: Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence.
abstract: Radiotherapy is one of the well-established therapeutic modalities for cancer treatment. However, the emergence of cells refractory to radiation is a major obstacle to successful treatment with radiotherapy. Many reports suggest that inhibitors targeting the mechanistic target of rapamycin (MTOR) can sensitize cancer cells to the effect of radiation, although by which mechanism MTOR inhibitors enhance the efficacy of radiation toward cancer cells remains to be elucidated. Our studies indicate that a potent and persistent activation of autophagy via inhibition of the MTOR pathway, even in cancer cells where autophagy is occurring, can trigger premature senescence, cellular proliferation arrest. Combined treatment of MTOR inhibitor and radiation induce heterochromatin formation, an irreversible growth arrest and an increase of senescence-associated GLB1 (β-galactosidase) activity, which appear to result from a constant activation of TP53 and a restoration in the activity of retinoblastoma 1 protein (RB1)-E2F1. Thus, this study provides evidence that promoting cellular senescence via inhibition of the MTOR pathway may serve as an avenue to augment radiosensitivity in cancer cells that initiate an autophagy-survival mode to radiotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology; Biomedical Research Center; University of Ulsan College of Medicine; Seoul, Korea; Biomedical Research Center; University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Hae Yun
authors.initials: HY
authors.lastname: Nam
authors.affiliation: Department of Otolaryngology; Ulsan University Hospital; Ulsan, Korea;
authors.forename: Myung Woul
authors.initials: MW
authors.lastname: Han
authors.affiliation: Department of Otolaryngology; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Hyo Won
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Biomedical Research Institute; Korea Institute of Science and Technology; Seoul, Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology; Biomedical Research Center; University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016160:Retinoblastoma Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: MTOR inhibitor; RB; autophagy; cellular senescence; irradiation