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Characterization of Gene Expression in ASS1-Deficient Breast Cancer Cells

ABSTRACT: Analysis of mechanism underlying the metabolic effects of ADI-PEG20 at gene expression level. The hypothesis tested in the present study was that ASS1-deficient breast cancer cells would be arginine-auxotrophs and would therefore be sensitive to arginine starvation. Results provide important information of the response of ASS1-deficient breast cancer cells to ADI-PEG20-treatment, such as the suppression of mRNAs encoding mitochondrial respiratory chain proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53838 | GEO | 2014/05/20

SECONDARY ACCESSION(S): PRJNA233499

REPOSITORIES: GEO

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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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Characterization of Gene Expression in ASS1-Deficient Breast Cancer Cells

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