title: Yet another function of p53--the switch that determines whether radiation-induced autophagy will be cytoprotective or nonprotective: implications for autophagy inhibition as a therapeutic strategy.
abstract: The influence of autophagy inhibition on radiation sensitivity was studied in human breast, head and neck, and non-small cell lung cancer cell lines, in cell lines that were either wild type or mutant/null in p53, and in cells where p53 was inducible or silenced. Whereas ionizing radiation promoted autophagy in all tumor cell lines studied, pharmacological inhibition of autophagy and/or genetic silencing of autophagy genes failed to influence sensitivity to radiation in p53 mutant Hs578t breast tumor cells, HN6 head and neck tumor cells, and H358 non-small cell lung cancer cells. The requirement for functional p53 in the promotion of cytoprotective autophagy by radiation was confirmed by the observation that radiation-induced autophagy was nonprotective in p53 null H1299 cells but was converted to the cytoprotective form with induction of p53. Conversely, whereas p53 wild-type HN30 head and neck cancer cells did show sensitization to radiation upon autophagy inhibition, HN30 cells in which p53 was knocked down using small hairpin RNA failed to be sensitized by pharmacological autophagy inhibition. Taken together, these findings indicate that radiation-induced autophagy can be either cytoprotective or nonprotective, a functional difference related to the presence or absence of function p53. Alternatively, these findings could be interpreted to suggest that whereas radiation can induce autophagy independent of p53 status, inhibition of autophagy promotes enhanced radiation sensitivity through a mechanism that requires functional p53. These observations are likely to have direct implications with respect to clinical efforts to modulate the response of malignancies to radiation through autophagy inhibition.
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Shweta
authors: S
authors: Chakradeo
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Khushboo
authors: K
authors: Sharma
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Aisha
authors: A
authors: Alhaddad
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Duaa
authors: D
authors: Bakhshwin
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Ngoc
authors: N
authors: Le
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Hisashi
authors: H
authors: Harada
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Wataru
authors: W
authors: Nakajima
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: W Andrew
authors: WA
authors: Yeudall
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Suzy V
authors: SV
authors: Torti
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut.
authors: Frank M
authors: FM
authors: Torti
authors: Departments of Medicine and Pharmacology and Toxicology, Massey Cancer Center (S.C., K.S., A.A., D.B., N.L., D.A.G.), and Department of Oral and Craniofacial Molecular Biology, School of Dentistry (H.H., W.N., W.A.Y.), Virginia Commonwealth University, Richmond, Virginia; and Departments of Molecular Biology and Biophysics (S.V.T.) and Medicine (F.M.T.), University of Connecticut Health Sciences, Farmington, Connecticut gewirtz@vcu.edu.
authors: David A
authors: DA
authors: Gewirtz
mesh_terms: D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D006801:Humans; D011836:Radiation Tolerance / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53