Abstract
The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the detoxification of carcinogens as well as clearance of anti-cancer drugs. In humans, 19 UGT family members have been identified and are expressed in a tissue specific manner throughout the body. However, the UGTs have not been previously characterized in melanocytes or melanoma. In the present study, UGT2B7, UGT2B10, and UGT2B15 were identified as being normally expressed in human melanocytes. The same three UGT family members were also expressed in the primary melanoma cell line WM115. No UGT expression was detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line examined. These results suggest that UGT expression is lost during melanoma progression. Treatment of WM3211 or metastatic melanoma cell lines with anti-cancer agents (including vemurafenib) induced expression of UGT2B7, UGT2B10 and UGT2B15 demonstrating that melanoma cells retain the ability to re-express these same three UGTs. The corresponding increase in glucuronidation activity in melanoma cells following anti-cancer treatment was also observed. Furthermore, knockdown of UGT2B7 in WM115 cells sensitized these cells to treatment by adriamycin and epirubicin indicating that UGT2B7 is involved in resistance to these drugs. However, knockdown of UGT2B7 had no effect on temozolomide toxicity. Taken together, these results clearly demonstrate a role for UGTs in melanoma etiology. Since the UGTs are drug metabolism enzymes, we propose that re-expression of the UGTs constitutes a previously unsuspected mechanism for intratumoral drug resistance in melanoma.
Highlights
The UGT family of enzymes catalyzes the glucuronidation of a wide range of xenobiotic and endogenous compounds
The same three UGTs were found to be expressed in the primary melanoma cell line WM115
UGT Expression in Human Melanocytes and Melanoma While UGT expression has previously been reported in the skin
Summary
The UGT family of enzymes catalyzes the glucuronidation of a wide range of xenobiotic and endogenous compounds. UGTs conjugate a glucuronic acid moiety to their substrates, altering the biological properties of the substrate and enhancing its excretion in urine or bile [1,2]. Glucuronidation converts substrates into less bioactive, more water soluble products facilitating their removal from the body. In this manner, the UGTs are integrally involved in the detoxification of many carcinogens, the clearance of drugs and the metabolism of a variety of endogenous substrates such as bilirubin, steroid hormones and bioactive lipids [1,2]. UGTs are primarily expressed in liver, they play vital roles in other tissues in the body. The role of the UGTs in skin, the largest organ in the body, has yet to be investigated
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