Back to Search
Start Over
Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis.
- Source :
-
Cell death & disease [Cell Death Dis] 2012 Jul 05; Vol. 3, pp. e342. Date of Electronic Publication: 2012 Jul 05. - Publication Year :
- 2012
-
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.
- Subjects :
- Arginine metabolism
Argininosuccinate Synthase genetics
Chloroquine pharmacology
DNA Methylation
Humans
Hydrolases therapeutic use
Lymphoma drug therapy
Lymphoma, T-Cell, Cutaneous drug therapy
Lymphoma, T-Cell, Cutaneous pathology
Microtubule-Associated Proteins metabolism
Polyethylene Glycols therapeutic use
Promoter Regions, Genetic
Tumor Cells, Cultured
Apoptosis drug effects
Argininosuccinate Synthase metabolism
Autophagy drug effects
Caspases metabolism
Hydrolases toxicity
Polyethylene Glycols toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 3
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 22764101
- Full Text :
- https://doi.org/10.1038/cddis.2012.83