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Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction

ABSTRACT: Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anti-cancer therapies.

INSTRUMENT(S): Liquid Chromatography MS - Alternating (LC-MS (Alternating))

SUBMITTER: Yue Qi

PROVIDER: MTBLS745 | MetaboLights | 2019-11-07

REPOSITORIES: MetaboLights

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Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction.

Cheng Chun-Ting CT Qi Yue Y Wang Yi-Chang YC Chi Kevin K KK Chung Yiyin Y Ouyang Ching C Chen Yun-Ru YR Oh Myung Eun ME Sheng Xiangpeng X Tang Yulong Y Liu Yun-Ru YR Lin H Helen HH Kuo Ching-Ying CY Schones Dustin D Vidal Christina M CM Chu Jenny C-Y JC Wang Hung-Jung HJ Chen Yu-Han YH Miller Kyle M KM Chu Peiguo P Yen Yun Y Jiang Lei L Kung Hsing-Jien HJ Ann David K DK

Communications biology 20181026

Defective arginine synthesis, due to the silencing of <i>argininosuccinate synthase 1</i> (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, argi ...[more]

PMID: 30393775

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Project description:One of the most common metabolic defects of cancer cells is the deficiency in arginine synthesis due to suppressed expression of argininosuccinate synthetase 1 (ASS1) which renders cancer cells auxotrophic to external arginine supply. Arginine deprivation has been effectively used as a treatment for leukemias, with several clinical trials on solid tumors underway. We previously showed that in prostate cancer arginine depletion induced mitochondrial dysfunction and excessive ROS production resulting in chromatin autophagy, nuclear DNA leakage, and cellular death, but the detailed mechanism of arginine starvation-induced cell death remains unclear. In this study, we demonstrated that arginine deprivation coordinately suppressed metabolic genes, including those responsible for mitochondrial oxidative phosphorylation (OXPHOS), nucleotide metabolism, and DNA repair. The consequent ROS production and impaired DNA damage response resulted in nuclear DNA leakage and cGAS-STING activation which is accompanied by upregulation of type I interferon response. We also showed that coordinated silencing of OXPHOS and DNA repair genes is caused in part by the depletion of α-ketoglutarate (αKG) and inactivation of histone demethylases. Supplementing cell-permeable dimethyl α-ketoglutarate (DMKG) both reduced repressive histone methylations and partially restored OXPHOS gene expressions, mitochondrial functions, and mitigated nuclear DNA leakage. Using our dietary arginine-restriction model, we demonstrate that arginine starvation slows prostate cancer growth with evidence of enhanced interferon responses and recruitment of immune cells. Our data suggests arginine starvation induces cell killing of ASS1-low cancer cells by metabolic depletion and epigenetic silencing of metabolic genes, leading to DNA damage and leakage. Resulting cGAS-STING activation may further enhance these killing effects. We used microarray to analyze the expression difference between control and arginine-depleted cells to find out what genes involved in the regulation of mitochondrial function and arginine deprivation-induced cell death.

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	MTBLS745	Other
	FILES	Other
	a_MTBLS745_mass_spectrometry.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS745_mass_spectrometry_v2_maf.tsv	Tabular