Aberrant regulation of argininosuccinate synthetase by TNF-α in human epithelial ovarian cancer

The pro‐inflammatory cytokine, tumour necrosis factor‐α, TNF‐α, is dysregulated in malignant compared with normal ovarian surface epithelium (OSE). Several epidemiological studies have associated inflammation with ovarian tumorigenesis, with TNF‐α playing a key role in modulating invasion, angiogenesis and metastasis. Here, we show that TNF‐α 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‐α‐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‐α in ovarian cancer cells, with significantly higher levels of AS in malignant compared with normal ovarian tissue. Increased co‐expression of AS and TNF‐α 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‐α and may provide an important molecular pathway linking inflammation and metabolism to ovarian tumorigenesis. © 2007 Wiley‐Liss, Inc.