title: Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells.
abstract: Autophagy is a novel response of cancer cells to ionizing radiation (IR) or chemotherapy, but its significance or mechanism remains largely elusive. Autophagy is characterized with the prominent formation of autophagic vacuoles in the cytoplasm. It is a protein degradation system that involves autophagic/lysosomal compartment. The process begins with sequestering a portion of the cytoplasm, forming the autophagosome. The autophagosome then fuses with the lysosome and lyses its contents. To study radiation-induced autophagy with specific molecules, we assessed changes in the expression of microtubule-associated protein light chain 3 (LC3) and its intracellular distribution after IR in comparison with starvation-induced autophagy. First, we showed that IR induced cell cycle arrest and autophagy, but not apoptosis, in human malignant glioma U373-MG cells. Type II LC3, that is specifically associated with the membrane of the autophagosome, increased after IR and amino acid starvation. Exogenous LC3 distributed on punctate structures, indicative of the formation of autophagosomes. Autophagy inhibitors, 3-methyladenine and bafilomycin A1, radiosensitized U373-MG cells. Furthermore, gammaH2AX foci, that show the extent of DNA double-strand breaks, were more pronounced and prolonged in the cells treated with IR and autophagy inhibitors than in those cells treated with IR only. Our results suggest that autophagy inhibitors may represent a new application of radiosensitization for malignant glioma cells.
authors.affiliation: Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ito
authors.forename: Shigeru
authors.initials: S
authors.lastname: Daido
authors.forename: Takao
authors.initials: T
authors.lastname: Kanzawa
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy / Q000528:radiation effects*; D001932:Brain Neoplasms / Q000473:pathology* / Q000532:radiotherapy*; D002453:Cell Cycle; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005910:Glioma / Q000473:pathology* / Q000532:radiotherapy*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011836:Radiation Tolerance
chemical_list: D004791:Enzyme Inhibitors; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; C040929:bafilomycin A1; D000225:Adenine