title: Catechol-O-methyltransferase-mediated metabolism of 4-hydroxyestradiol inhibits the growth of human renal cancer cells through the apoptotic pathway.
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.
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA.
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Jan
authors.initials: J
authors.lastname: Liu
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Mohd S
authors.initials: MS
authors.lastname: Zaman
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002394:Catechol O-Methyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002393:Estrogens, Catechol; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D000097642:GADD45 Proteins
chemical_list: D002394:Catechol O-Methyltransferase; D018797:Cell Cycle Proteins; D004958:Estradiol; D002393:Estrogens, Catechol; D009687:Nuclear Proteins; D012333:RNA, Messenger; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C045018:4-methoxyestradiol; C014036:4-hydroxyestradiol