title: Aberrant regulation of argininosuccinate synthetase by TNF-alpha in human epithelial ovarian cancer.
abstract: The pro-inflammatory cytokine, tumour necrosis factor-alpha, TNF-alpha, is dysregulated in malignant compared with normal ovarian surface epithelium (OSE). Several epidemiological studies have associated inflammation with ovarian tumorigenesis, with TNF-alpha playing a key role in modulating invasion, angiogenesis and metastasis. Here, we show that TNF-alpha also induces expression of arate-limiting enzyme in arginine synthesis, argininosuccinate synthetase (AS), thereby linking inflammation with several arginine-dependent metabolic pathways, implicated in accelerated carcinogenesis and tumour progression. Having identified AS mRNA induction in TNF-alpha-treated IGROV-1 ovarian cancer cells, using RNA-arbitrarily primed-PCR, we then observed differential regulation of AS mRNA and protein in malignant, compared with normal, OSE cells. A cDNA cancer profiling array with matched normal ovarian and ovarian tumour samples revealed increased expression of AS mRNA in the latter. Moreover, AS protein co-localised with TNF-alpha in ovarian cancer cells, with significantly higher levels of AS in malignant compared with normal ovarian tissue. Increased co-expression of AS and TNF-alpha mRNA was also observed in 2 other epithelial tumours, non-small cell lung and stomach cancer, compared with normal corresponding tissues. In summary, high levels of AS expression, which may be required for several arginine-dependent processes in cancer, including the production of nitric oxide, proline, pyrimidines and polyamines, is regulated by TNF-alpha and may provide an important molecular pathway linking inflammation and metabolism to ovarian tumorigenesis.
authors.affiliation: Cancer Research UK, Translational Oncology Laboratory, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom. peter.szlosarek@bartsandthelondon.nhs.uk
authors.forename: Peter W
authors.initials: PW
authors.lastname: Szlosarek
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Grimshaw
authors.forename: George D
authors.initials: GD
authors.lastname: Wilbanks
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
authors.forename: Julia L
authors.initials: JL
authors.lastname: Wilson
authors.forename: Frances
authors.initials: F
authors.lastname: Burke
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
mesh_terms: D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006262:Health; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001124:Argininosuccinate Synthase