title: Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis.
abstract: Tumours lacking argininosuccinate synthetase-1 (ASS1) are auxotrophic for arginine and sensitive to amino-acid deprivation. Here, we investigated the role of ASS1 as a biomarker of response to the arginine-lowering agent, pegylated arginine deiminase (ADI-PEG20), in lymphoid malignancies. Although ASS1 protein was largely undetectable in normal and malignant lymphoid tissues, frequent hypermethylation of the ASS1 promoter was observed specifically in the latter. A good correlation was observed between ASS1 methylation, low ASS1 mRNA, absence of ASS1 protein expression and sensitivity to ADI-PEG20 in malignant lymphoid cell lines. We confirmed that the demethylating agent 5-Aza-dC reactivated ASS1 expression and rescued lymphoma cell lines from ADI-PEG20 cytotoxicity. ASS1-methylated cell lines exhibited autophagy and caspase-dependent apoptosis following treatment with ADI-PEG20. In addition, the autophagy inhibitor chloroquine triggered an accumulation of light chain 3-II protein and potentiated the apoptotic effect of ADI-PEG20 in malignant lymphoid cells and patient-derived tumour cells. Finally, a patient with an ASS1-methylated cutaneous T-cell lymphoma responded to compassionate-use ADI-PEG20. In summary, ASS1 promoter methylation contributes to arginine auxotrophy and represents a novel biomarker for evaluating the efficacy of arginine deprivation in patients with lymphoma.
authors: Barts Cancer Institute, Queen Mary University of London, Centre for Molecular Oncology, London, UK.
authors: B
authors: B
authors: Delage
authors: P
authors: P
authors: Luong
authors: L
authors: L
authors: Maharaj
authors: C
authors: C
authors: O'Riain
authors: N
authors: N
authors: Syed
authors: T
authors: T
authors: Crook
authors: E
authors: E
authors: Hatzimichael
authors: A
authors: A
authors: Papoudou-Bai
authors: T J
authors: TJ
authors: Mitchell
authors: S J
authors: SJ
authors: Whittaker
authors: R
authors: R
authors: Cerio
authors: J
authors: J
authors: Gribben
authors: N
authors: N
authors: Lemoine
authors: J
authors: J
authors: Bomalaski
authors: C-F
authors: CF
authors: Li
authors: S
authors: S
authors: Joel
authors: J
authors: J
authors: Fitzgibbon
authors: L-T
authors: LT
authors: Chen
authors: P W
authors: PW
authors: Szlosarek
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D019175:DNA Methylation; D006801:Humans; D006867:Hydrolases / Q000627:therapeutic use / Q000633:toxicity*; D008223:Lymphoma / Q000188:drug therapy; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011092:Polyethylene Glycols / Q000627:therapeutic use / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D011092:Polyethylene Glycols; D002738:Chloroquine; D001120:Arginine; D006867:Hydrolases; D020169:Caspases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase