期刊
CELL REPORTS
卷 16, 期 6, 页码 1604-1613出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.06.097
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资金
- British Lung Foundation [APG12-10, MESO15-12]
- June Hancock Mesothelioma Research Fund
- Cancer Research UK [C16420/A18066]
- Barry Reed Cancer Research Fund
- British Lung Foundation [APG12-10, MESO15-12] Funding Source: researchfish
Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting. We have generated a model of ADI-PEG20 resistance in mesothelioma cells. This resistance is mediated through re-expression of ASS1 via demethylation of the ASS1 promoter. Through coordinated transcriptomic andmetabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamine metabolites, together with a compensatory increase in the expression of polyamine biosynthetic enzymes. Upon arginine deprivation, polyamine metabolites are decreased in the ASS1-deficient cells and in plasma isolated from ASS1-deficient mesothelioma patients. We identify a synthetic lethal dependence between ASS1 deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers.
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