Catechol-O-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, Yuichiro Tanaka

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10 Scopus citations

Abstract

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-OHE 2), growth is inhibited by apoptotic cell death. We also found that COMT overexpression combined with 4-OHE 2 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-OHE 2. Finally, 4-methoxyestradiol fully reproduces the antiproliferative function of COMT with 4-OHE 2 by promoting GADD45α induction. Together, these findings show that COMT in the presence of 4-OHE 2 prevents RCC cell proliferation by enhancing apoptosis and that GADD45α plays a critical role in the COMT-mediated inhibition of RCC.

Original languageEnglish (US)
Pages (from-to)420-426
Number of pages7
JournalCarcinogenesis
Volume33
Issue number2
DOIs
StatePublished - Feb 8 2012
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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    Chang, I., Liu, J., Majid, S., Saini, S., Zaman, M. S., Yamamura, S., Shahryari, V., Chiyomaru, T., Deng, G., Dahiya, R., & Tanaka, Y. (2012). Catechol-O-methyltransferase-mediated metabolism of 4-hydroxyestradiol inhibits the growth of human renal cancer cells through the apoptotic pathway. Carcinogenesis, 33(2), 420-426. https://doi.org/10.1093/carcin/bgr294