Back to Search
Start Over
Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer
- Source :
- International Journal of Cancer. 125:1454-1463
- Publication Year :
- 2009
- Publisher :
- Wiley, 2009.
-
Abstract
- Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down-regulation of expression of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum-based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum-based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine-depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse-free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer.
- Subjects :
- Cancer Research
medicine.medical_specialty
Paclitaxel
endocrine system diseases
Arginine
Immunoblotting
Argininosuccinate synthase
Argininosuccinate Synthase
Carboplatin
chemistry.chemical_compound
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Tumor Cells, Cultured
medicine
Humans
Gene Silencing
Epigenetics
Promoter Regions, Genetic
Ovarian Neoplasms
Cisplatin
Cell Death
biology
Cancer
DNA Methylation
Middle Aged
medicine.disease
female genital diseases and pregnancy complications
Cystadenocarcinoma, Serous
Gene Expression Regulation, Neoplastic
Survival Rate
Endocrinology
Oncology
chemistry
Drug Resistance, Neoplasm
DNA methylation
biology.protein
Cancer research
Female
Ovarian cancer
medicine.drug
Subjects
Details
- ISSN :
- 10970215 and 00207136
- Volume :
- 125
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi.dedup.....8625b231ffa628e81da92bd91a4af498