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.

Given the variability in presentation of 22q11.2DS, a highly individualized approach is necessary. If possible, it is recommended that children with 22q11.2DS

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. We have demonstrated that three UGT family members (UGT2B7, UGT2B10 and UGT2B15) are normally expressed in human melanocytes isolated form neonatal foreskin. Further, we screened several primary and metastatic melanoma cells lines for UGT expression. 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 of the four metastatic melanoma cell line assayed suggesting that loss of UGT expression occurs during melanoma progression. To elucidate if ultraviolet (UV) light could be the underlying cause to the disappearance of UGTs in melanoma progression, human melanocytes were subjected to UV-B radiation at low and high (sunburn) doses. Melanocytes were collected at 1, 5 and 24 Hrs post UV-B treatment and UGT expression was analyzed by quantitative real-time PCR. Expression of UGT2B7, UGT2B10 and UGT2B15 all was significantly reduced in response to both low and high dose UV-B. In general, loss of UGT expression was observed even at 1 hour after exposure, reached maximal low levels at 5 hours and started to return to normal levels at 24 hours post exposure. We hypothesize that reduction of UGT expression in melanocytes following a sunburn would increase an individuals risk for melanoma since the UGTs detoxify environmental carcinogens. This hypothesis is consistent with a causative role for UV in melanoma in which ‘classical’ UV-induced DNA damage is not observed; a problem that has long puzzled investigators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 268. doi:1538-7445.AM2012-268