Long-term exposure to estrogen and its metabolites may play an important role in renal cell carcinogenesis. Catechol-O-methyltransferase (COMT) participates in the estrogen metabolism pathway by neutralizing toxic substances. Although reduced COMT activity has been suggested to be a risk factor for estrogen-associated cancers, no studies have investigated the biological significance of COMT in the pathogenesis of human renal cell cancers (RCC). Using quantitative PCR, Western blotting and immunohistochemical staining, we initially found that COMT levels are significantly decreased in human RCC tissues and cells suggesting a suppressive role of COMT in tumor development. However, transient over-expression of COMT has no effect on the proliferation, apoptosis and cell cycle progression of RCC cell lines. In contrast, when cells over-expressing COMT are treated with its substrate 4-hydroxyestradiol (4-OHE2), growth is inhibited by apoptotic cell death. We also found that COMT over-expression combined with 4-OHE2 induces up-regulation of growth arrest- and DNA damage-inducible protein ≤ (GADD45α). We further show that down-regulation of GADD45α by a siRNA-mediated approach inhibits cell death, indicating the essential role of GADD45α in the underlying mechanism of COMT action in response to 4-OHE2. Finally, 4-methoxyestradiol (4-ME) fully reproduces the anti-proliferative function of COMT with 4-OHE2 by promoting GADD45α induction. Together, our study shows that COMT in the presence of 4-OHE2 prevents RCC cell proliferation by enhancing apoptosis, and that GADD45α plays a critical role in the COMT-mediated inhibition of RCC. These findings will provide new direction for the biomarker detection and corresponding treatment in the prevention of human RCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1860. doi:1538-7445.AM2012-1860