title: Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy.
abstract: Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.
authors.affiliation: Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817; NSF Center for Biophotonics Science and Technology, University of California, Davis, CA 95817; Integrated Laboratory, Center of Translational Medicine and Graduate Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan 110, Republic of China; and.
authors.forename: Chun A
authors.initials: CA
authors.lastname: Changou
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biology and.
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.affiliation: Integrated Laboratory, Center of Translational Medicine and Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817; NSF Center for Biophotonics Science and Technology, University of California, Davis, CA 95817;
authors.forename: Frank Y S
authors.initials: FY
authors.lastname: Chuang
authors.affiliation: Department of Molecular and Cellular Biology and.
authors.forename: R Holland
authors.initials: RH
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of California, Davis, CA 95817;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bold
authors.affiliation: Integrated Laboratory, Center of Translational Medicine and Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010; dann@coh.org hkung@nhri.org.tw.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
authors.affiliation: Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817; Integrated Laboratory, Center of Translational Medicine and National Health Research Institutes, Taipei, Taiwan 115, Republic of China dann@coh.org hkung@nhri.org.tw.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001120:Arginine / Q000172:deficiency / Q000378:metabolism*; D001124:Argininosuccinate Synthase / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009685:Nuclear Envelope / Q000187:drug effects / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D004273:DNA, Neoplasm; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase
keywords: ADI-PEG20; arginine auxotrophy; cancer therapy; metabolic stress; prostate cancer