title: A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles.
abstract: The mechanisms underlying neoplastic epithelial cell killing by ionizing radiation are largely unknown. We discovered a novel response to radiation manifested by autophagy and the development of acidic vesicular organelles (AVO). Acidification of AVO was mediated by the vacuolar H+-ATPase. Staining with the lysosomotropic agent acridine orange enabled us to quantify AVO accumulation and to demonstrate their time- and dose-dependent appearance. The appearance of AVO occurred in the presence of the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethyl ketone, but was inhibited by 3-methyladenine, an inhibitor of autophagy. The accretion of AVO in surviving progenies of irradiated cells, and the increased incidence of clonogenic death after inhibition of vacuolar H+-ATPase suggest that formation of acidic organelles represents a novel defense mechanism against radiation damage.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: S
authors.initials: S
authors.lastname: Paglin
authors.forename: T
authors.initials: T
authors.lastname: Hollister
authors.forename: T
authors.initials: T
authors.lastname: Delohery
authors.forename: N
authors.initials: N
authors.lastname: Hackett
authors.forename: M
authors.initials: M
authors.lastname: McMahill
authors.forename: E
authors.initials: E
authors.lastname: Sphicas
authors.forename: D
authors.initials: D
authors.lastname: Domingo
authors.forename: J
authors.initials: J
authors.lastname: Yahalom
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000528:radiation effects*; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000528:radiation effects* / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000235:genetics / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008854:Microscopy, Electron; D006180:Proton-Translocating ATPases / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D004273:DNA, Neoplasm; C025946:3-methyladenine; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases; D000225:Adenine