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

被引:105
作者
Delage, B. [1 ]
Luong, P. [1 ]
Maharaj, L. [2 ]
O'Riain, C. [2 ]
Syed, N. [3 ]
Crook, T. [4 ]
Hatzimichael, E. [5 ]
Papoudou-Bai, A. [6 ]
Mitchell, T. J. [7 ]
Whittaker, S. J. [7 ]
Cerio, R. [8 ]
Gribben, J. [2 ]
Lemoine, N. [1 ]
Bomalaski, J. [9 ]
Li, C-F [10 ]
Joel, S. [2 ]
Fitzgibbon, J. [2 ]
Chen, L-T [11 ,12 ]
Szlosarek, P. W. [1 ,8 ]
机构
[1] Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, John Vane Sci Ctr, London EC1M 6BQ, England
[2] Queen Mary Univ London, Barts Canc Inst, Ctr Haematooncol, John Vane Sci Ctr, London EC1M 6BQ, England
[3] Univ London Imperial Coll Sci Technol & Med, London, England
[4] Univ Dundee, Dundee Canc Ctr, Ninewells Hosp, Dundee, Scotland
[5] Univ Hosp Ioannina, Dept Haematol, Ioannina, Greece
[6] Univ Hosp Ioannina, Dept Pathol, Ioannina, Greece
[7] Kings Coll London, St Johns Inst Dermatol, London WC2R 2LS, England
[8] Barts & London, Dept Dermatol Oncol, London, England
[9] Polaris Grp, San Diego, CA USA
[10] Chi Mei Med Ctr, Dept Pathol, Tainan, Taiwan
[11] Kaohsiung Med Univ, Dept Internal Med, Kaohsiung Med Univ Hosp, Kaohsiung, Taiwan
[12] Natl Hlth Res Inst, Natl Inst Canc Res, Tainan 70456, Taiwan
来源
CELL DEATH & DISEASE | 2012年 / 3卷
关键词
lymphoma; ASS1 promoter methylation; arginine; ADI-PEG20; autophagy; chloroquine; T-CELL RESPONSES; HEPATOCELLULAR-CARCINOMA; FOLLICULAR LYMPHOMA; PHASE-II; CANCER; EXPRESSION; THERAPY; DEPRIVATION; DEFICIENCY; RECEPTOR;
D O I
10.1038/cddis.2012.83
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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. Cell Death and Disease (2012) 3, e342; doi:10.1038/cddis.2012.83; published online 5 July 2012
引用
收藏
页码:e342 / e342
页数:9
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