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Role of UDP-glucose Dehydrogenase in Prostate Cancer Therapeutic Resistance
Prostate cancer is the most frequently diagnosed male cancer and the second leading cause of cancer related death in U.S. men. Treatment of locally advanced and metastatic tumors involves androgen deprivation therapy. Despite this treatment, more aggressive and metastatic tumors recur in a low circulating androgen environment. Availability of hormones in prostate epithelial cells are limited by their inactivation pathways. The enzymes that catalyze the inactivation reaction are UDP-glucuronsyltransferases (UGTs), which catalyze the covalent conjugation of the hormone using UDP-glucuronate as a precursor. Our lab has shown that the enzyme UDP-glucose dehydrogenase (UGDH), which provides this precursor, is upregulated by androgen and drives hormone elimination even in the presence of suppressed UGT. The goal of this work was to evaluate the effect of differential UGDH expression on androgen sensitivity in culture, to examine the underlying mechanisms responsible for directed channeling of UDP-glucuronate, and to evaluate UGDH as a target to control UDP-glucuronate partitioning. To evaluate the effect of differential UGDH expression on androgen sensitivity in culture, we used an isogenic LNCaP human prostate tumor cell culture model for androgen-dependent (LNCaP33) versus castration-resistant (LNCaP81) prostate cancer. We showed that the androgen-dependent line produced significantly more steroid glucuronides and exhibited a potent response to androgen exposure relative to castration-resistant cells, which channeled UDP-glucuronate precursors to producing proteoglycans as measured by increased surface expression of Notch1. To examine the underlying mechanisms responsible for directed channeling of UDP-glucuronate, we used the isogenic culture model to compare the impact of UGDH manipulation on androgen receptor-mediated gene expression, UDP-sugar content and the proliferative capacity of tumor cells. UGDH overexpression in LNCaP33 cells led to increased expression of UGT2B17 and Notch1, blunted responses to exogenous androgen, and increased growth rate compared to controls, consistent with the role and response of UGDH in castration-resistant cells. Furthermore, co-immunoprecipitation of FoxA1, the transcription factor necessary for UGT expression, revealed greater pulldown of AR in LNCaP33 relative to LNCaP81 cells. These results provide novel insights to metabolite-mediated gene expression, explain biomarker profiles associated with loss of androgen sensitivity, and improve the understanding of prostate cancer recurrence mechanisms following hormone deprivation therapy.
Zimmer, Brenna M, "Role of UDP-glucose Dehydrogenase in Prostate Cancer Therapeutic Resistance" (2018). ETD collection for University of Nebraska - Lincoln. AAI10843346.