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UBC Theses and Dissertations

Utilizing catalytic Topo II inhibitor to target reestablished androgen receptor signaling in castration-resistant prostate cancer Li, Haolong

Abstract

Prostate cancer, the most common malignancy in Canadian men, is a leading cause of cancer-related male mortality. Androgen deprivation therapy is the first-line treatment for advanced prostate cancer. However, a fatal relapse to androgen deprivation therapy is inevitable, which is often characterized by the establishment of an androgen-independent AR signalling that drives the disease to the lethal castration-resistant prostate cancer (CRPC) stage. Defining the mechanisms that promote the reestablishment of AR signaling including the androgen independence is important for therapy development and disease control. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms and its expression has been reported to increase after antiandrogen treatment. Whether UGT2B17 plays a role in the progression of CRPC is unclear. In this work, we demonstrated that the higher expression of UGT2B17 protein is associated with higher Gleason scores, increased metastasis and CRPC progression in prostate tumors. The expression and activity of UGT2B17 were also higher in androgen-independent cell lines compared to androgen-dependent cell lines. Overexpression of UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Furthermore, UGT2B17 not only suppressed androgen-dependent AR transcriptional activity but also enhanced androgen-independent AR transcriptional activity, mainly through activating the c-Src kinase. These results indicate that the UGT2B17-Src-AR signaling contributes to the reestablished AR signaling and expedites CRPC progression and blocking the UGT2B17-Src-AR cascade will be beneficial for overcoming the resistance in CRPC patients. Accordingly, pharmacological targeting of the catalytic domain of DNA topoisomerase II (Topo II), which is known to be essential for AR-mediated transcriptional control, can completely block the transcriptional activity of reestablished AR, mutant ARs and AR splicing variants. Targeting Topo II also strengthened the efficacy of current anti-androgens in suppressing wild type AR activities. Furthermore, catalytic Topo II inhibitors inhibited CRPC and enzalutamide-resistant prostate cancer cell growth and xenograft progression. Overall, my doctoral thesis demonstrates that the UGT2B17-Src-AR signaling axis contributes to the reestablished AR signaling and expedites CRPC progression, and that applying catalytic Topo II inhibitors can block the transcriptional activity of reestablished AR signaling and suppress CRPC progression.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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