Noncanonical functions of UGT2B17 promote castration-resistant prostate cancer progression
Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia H.Y. Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong
Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia H.Y. Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong
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Research Article Clinical Research Oncology

Noncanonical functions of UGT2B17 promote castration-resistant prostate cancer progression

Abstract

Androgen deprivation therapy is the primary treatment for advanced prostate tumors. While initially effective, tumor progression to the therapy-resistant stage is inevitable. Paradoxically, UDP glucuronosyltransferase family 2 member B17 (UGT2B17), the key enzyme responsible for androgen catabolism in prostate tumor cells, is upregulated in therapy-resistant tumors, though its role in tumor progression remains unclear. Here, we demonstrate that UGT2B17 possesses multiple oncogenic functions independent of androgen catabolism. It modulates protein-folding pathways, allowing tumor cells to endure therapy-induced stress. UGT2B17 also regulates transcription associated with cell division and the DNA damage response, enabling unchecked cell proliferation. Targeting the newly identified UGT2B17 functions using a combination of inhibitors reduced tumor growth in therapy-resistant tumor models, highlighting a promising therapeutic strategy. Collectively, these findings reveal a mechanism by which prostate tumors exploit UGT2B17 to evade therapy and highlight its potential as a therapeutic target in advanced prostate cancer.

Authors

Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia H.Y. Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong

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Figure 6

The UGT2B17/Src signaling regulates cell mitosis and CRPC xenograft growth.

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The UGT2B17/Src signaling regulates cell mitosis and CRPC xenograft grow...
(A) LNCaP95 and LN95(KO) cells were treated with three Src inhibitors (top). LN95(KO) cells were transfected with control, constitutively active Src(Y530F), or kinase-dead Src(K259M) (bottom). Cell proliferation at day 3 was measured and normalized to that at day 0. (B) LNCaP95, MR49F, and their UGT2B17-knockout derivatives were treated with 10 nM dasatinib. Total and phosphorylated ATM and ATR were assessed by immunoblotting. Densitometric ratios of phospho-ATM/ATM and phospho-ATR/ATR were calculated and plotted. (C) LN95(KO) cells transfected with control, Src(Y530F), or Src(K259M) were analyzed by immunoblotting for Src, pSrc(Y419), ATM, pATM(S1981), ATR, pATR(T1989), and cPARP. Phosphorylation levels were quantified relative to total protein levels. (D and E) LNCaP95 and LN95(KO) cells were synchronized at the G1/S phase (D) or at the G2/M phase (E). Cells were then treated with vehicle or 10 nM dasatinib and allowed to recover for the indicated times. Cell-cycle distributions were determined by FACS. (F) LNCaP95 and LNCaP(UGT) cells were treated with increasing concentrations of dasatinib and AZD6738 for 3 days. Cell proliferation was measured and used to assess drug-drug interactions. (G) Castrated nude mice bearing LNCaP95 xenografts were treated with vehicle, dasatinib (10 mg/kg), AZD6738 (25 mg/kg), or the combination (n = 6/group). Tumor volumes were measured weekly. (H and I) After 4 weeks of treatment, tumors from each group were collected to evaluate Src, pSrc(Y419), ATR, pATR(T1989), and γH2AX (Ser139) by immunoblotting (H) and IHC (I). Experiments in A–F were repeated three times with similar results. Data are presented as mean ± SEM. Statistical analyses were performed using two-way ANOVA (A top, B, D, E, G) or one-way ANOVA (A bottom). *P < 0.05, **P < 0.01, ***P < 0.001.