Abstract 2553: Characterization of the UDP-Glucuronosyltransferases in melanocytes and melanoma

Abstract

Abstract The UDP-glucuronosyltransferase (UGT) family of enzymes catalyzes the glucuronidation of a variety of endogenous compounds such as bilirubin and steroid hormones, as well as xenobiotics including chemotherapeutic agents and environmental carcinogens. Glucuronidation of these substrates inactivates them by making them more hydrophilic and easily excreted. UGTs are expressed primarily in the liver, but are also expressed in several extra-hepatic tissues including prostate, breast, colon, lung, brain, kidney, bladder and ovary. However, there have been no reports measuring UGTs in melanocytes or melanoma. We screened several primary melanocyte cultures from neonatal foreskin as well as several primary and metastatic melanoma cell lines for UGT expression by RT-PCR. Three UGT family members, UGT2B7, UGT2B10 and UGT2B15, were found to be expressed in melanocytes. Interestingly, of all the melanoma cell lines screened only WM115, a primary melanoma, had UGT expression. Again, only UGT2B7, UGT2B10 and UGT2B15 were detected. UGT expression was not detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line assayed suggesting that loss of UGT expression occurs during melanoma progression. Treatment of WM3211 cells with temozolomide, currently indicated for treatment of metastatic melanoma, induced expression of UGT2B7, UGT2B10 and UGT2B15. Similar induction of these UGTs was observed in response to adriamycin or epirubicin treatment of WM3211 cells. Furthermore, induction of UGT2B7, UGT2B10 and UGT2B15 in response to epirubicin was also observed in the metastatic melanoma cell line SKmel28. Since the UGTs are Phase II xenobiotic metabolism enzymes, we hypothesize that the upregulation of the UGTs in melanoma cells in response to chemotherapeutic agents is a potential mechanism for the well documented drug resistance observed in this malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2553.