Promoter Methylation of Argininosuccinate synthetase-1 Sensitises Lymphomas to Arginine Deiminase Treatment, Autophagy and Caspase-Dependent Apoptosis

Cell Death Dis. 2012 Jul 5;3(7):e342. doi: 10.1038/cddis.2012.83.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Arginine / metabolism
  • Argininosuccinate Synthase / genetics
  • Argininosuccinate Synthase / metabolism*
  • Autophagy / drug effects*
  • Caspases / metabolism*
  • Chloroquine / pharmacology
  • DNA Methylation
  • Humans
  • Hydrolases / therapeutic use
  • Hydrolases / toxicity*
  • Lymphoma / drug therapy
  • Lymphoma, T-Cell, Cutaneous / drug therapy
  • Lymphoma, T-Cell, Cutaneous / pathology
  • Microtubule-Associated Proteins / metabolism
  • Polyethylene Glycols / therapeutic use
  • Polyethylene Glycols / toxicity*
  • Promoter Regions, Genetic
  • Tumor Cells, Cultured

Substances

  • Microtubule-Associated Proteins
  • light chain 3, human
  • Polyethylene Glycols
  • Chloroquine
  • Arginine
  • Hydrolases
  • Caspases
  • ADI PEG20
  • Argininosuccinate Synthase