TY - JOUR
T1 - Inhibition of the Wnt/b-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer
AU - Zhang, Zhuangzhuang
AU - Cheng, Lijun
AU - Li, Jie
AU - Farah, Elia
AU - Atallah, Nadia M.
AU - Pascuzzi, Pete E.
AU - Gupta, Sanjay
AU - Liu, Xiaoqi
N1 - Publisher Copyright:
© 2018 AACR.
PY - 2018/6/15
Y1 - 2018/6/15
N2 - Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/β-catenin pathway and its interaction with AR play a major role in acquisition of enzalutamide resistance. To validate the finding, we show upregulation of b-catenin and AR in enzalutamide-resistant cells, partially due to reduction of b-TrCP-mediated ubiquitination. Although activation of the Wnt/β-catenin pathway in enzalutamide- sensitive cells led to drug resistance, combination of b-catenin inhibitor ICG001 with enzalutamide inhibited expression of stem-like markers, cell proliferation, and tumor growth synergistically in various models. Analysis of clinical datasets revealed a molecule pattern shift in different stages of prostate cancer, where we detected a significant correlation between AR and b-catenin expression. These data identify activation of the Wnt/β-catenin pathway as a major mechanism contributing to enzalutamide resistance and demonstrate the potential to stratify patients with high risk of said resistance. Significance: Wnt/β-catenin inhibition resensitizes prostate cancer cells to enzalutamide.
AB - Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/β-catenin pathway and its interaction with AR play a major role in acquisition of enzalutamide resistance. To validate the finding, we show upregulation of b-catenin and AR in enzalutamide-resistant cells, partially due to reduction of b-TrCP-mediated ubiquitination. Although activation of the Wnt/β-catenin pathway in enzalutamide- sensitive cells led to drug resistance, combination of b-catenin inhibitor ICG001 with enzalutamide inhibited expression of stem-like markers, cell proliferation, and tumor growth synergistically in various models. Analysis of clinical datasets revealed a molecule pattern shift in different stages of prostate cancer, where we detected a significant correlation between AR and b-catenin expression. These data identify activation of the Wnt/β-catenin pathway as a major mechanism contributing to enzalutamide resistance and demonstrate the potential to stratify patients with high risk of said resistance. Significance: Wnt/β-catenin inhibition resensitizes prostate cancer cells to enzalutamide.
UR - http://www.scopus.com/inward/record.url?scp=85048725524&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048725524&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-3006
DO - 10.1158/0008-5472.CAN-17-3006
M3 - Article
C2 - 29700003
AN - SCOPUS:85048725524
SN - 0008-5472
VL - 78
SP - 3147
EP - 3162
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -
