Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis

• Published in: Cell death & disease Vol. 3; no. 7; p. e342
• Main Authors: Delage, B, Luong, P, Maharaj, L, O’Riain, C, Syed, N, Crook, T, Hatzimichael, E, Papoudou-Bai, A, Mitchell, T J, Whittaker, S J, Cerio, R, Gribben, J, Lemoine, N, Bomalaski, J, Li, C-F, Joel, S, Fitzgibbon, J, Chen, L-T, Szlosarek, P W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2012; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/80/458/1648; 631/80/82/39; 692/699/67/1990/291; Antibodies; Apoptosis - drug effects; Arginine - metabolism; Argininosuccinate Synthase - genetics; Argininosuccinate Synthase - metabolism; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Caspases - metabolism; Cell Biology; Cell Culture; Chloroquine - pharmacology; DNA Methylation; Humans; Hydrolases - therapeutic use; Hydrolases - toxicity; Immunology; Life Sciences; Lymphoma - drug therapy; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - pathology; Microtubule-Associated Proteins - metabolism; Original; original-article; Polyethylene Glycols - therapeutic use; Polyethylene Glycols - toxicity; Promoter Regions, Genetic; Tumor Cells, Cultured; chloroquine; ADI-PEG20; arginine; autophagy; promoter methylation; lymphoma
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2012.83

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.