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A Novel Response of Cancer Cells to Radiation Involves Autophagy and Formation of Acidic Vesicles¹

Department of Radiation Oncology [S. P., T. H., N. H., M. M., J. Y.], and Flow Cytometry Core Facility [T. D., D. D.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and the Electron Microscopy Service, Rockefeller University, New York, New York 10021 [E. S.]

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.

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