title: Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells.
abstract: Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.|Department of Medical Oncology, Zhejiang University School of Medicine, Hangzhou 310012, China.
authors.forename: Fuming
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Li-Jiuan
authors.initials: LJ
authors.lastname: Shen
authors.affiliation: Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310012, China.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Gaur
authors.affiliation: Life & Environmental Sciences Unit, University of California, Merced, Merced, CA 95343, USA.|Ethel Percy Andrus Gerontology Center, Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310012, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310012, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.|Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310012, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.|Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA.|National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.|Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D001124:Argininosuccinate Synthase / Q000172:deficiency*; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000494:pharmacology; D011379:Prognosis; D023041:Xenograft Model Antitumor Assays
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase