Journal Article

Catechol-<i>O</i>-methyltransferase-mediated metabolism of 4-hydroxyestradiol inhibits the growth of human renal cancer cells through the apoptotic pathway

Inik Chang, Jan Liu, Shahana Majid, Sharanjot Saini, Mohd S. Zaman, Soichiro Yamamura, Varahram Shahryari, Takeshi Chiyomaru, Guoren Deng, Rajvir Dahiya and Yuichiro Tanaka

in Carcinogenesis

Volume 33, issue 2, pages 420-426
Published in print February 2012 | ISSN: 0143-3334
Published online December 2011 | e-ISSN: 1460-2180 | DOI:
Catechol-O-methyltransferase-mediated metabolism of 4-hydroxyestradiol inhibits the growth of human renal cancer cells through the apoptotic pathway

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  • Clinical Cytogenetics and Molecular Genetics


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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 (RCCs). We initially found that COMT levels are significantly decreased in human RCC tissues and cells suggesting it plays a suppressive role in tumor development. However, transient overexpression of COMT has no functional effect on RCC cell lines. In contrast, when cells overexpressing COMT are treated with its substrate 4-hydroxyestradiol (4-OHE2), growth is inhibited by apoptotic cell death. We also found that COMT overexpression combined with 4-OHE2 induces upregulation of growth arrest- and DNA damage-inducible protein α (GADD45α). We further show that downregulation of GADD45α by a small interfering RNA-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 fully reproduces the antiproliferative function of COMT with 4-OHE2 by promoting GADD45α induction. Together, these findings show 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.

Journal Article.  5430 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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