Divergent Androgen Receptor and Beta-Catenin Signaling in Prostate Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Prostate cancer progression to castration-resistant prostate cancer (CRPC) remains a lethal challenge.
• Targeting the androgen receptor (AR) pathway alone is insufficient due to tumor heterogeneity and pathway mis-regulation in CRPC.
• The Wnt/β-catenin pathway's role in CRPC is under investigation.

Purpose of the Study:

• To investigate the activation of the Wnt/β-catenin pathway in prostate cancer cells following androgen deprivation.
• To determine if Wnt/β-catenin pathway activation promotes androgen-independent growth.
• To evaluate the therapeutic potential of inhibiting the Wnt/β-catenin pathway in combination with antiandrogen therapy for CRPC.

Main Methods:

• Assessed Wnt pathway activation using a Wnt-reporter assay in androgen-independent prostate cancer cells.
• Investigated the interaction between β-catenin and TCF4.
• Evaluated the effect of Wnt/β-catenin pathway inhibition on prostate cancer cell sensitivity to enzalutamide.
• Tested combined treatment of enzalutamide and a Wnt/β-catenin inhibitor on both androgen-dependent and -independent prostate cancer cells.

Main Results:

• Androgen-independent prostate cancer cells showed increased Wnt pathway activation.
• Inhibition of the Wnt/β-catenin pathway enhanced sensitivity to enzalutamide.
• Combined treatment with enzalutamide and a Wnt/β-catenin inhibitor led to significant growth repression in both androgen-dependent and -independent prostate cancer cells.

Conclusions:

• The Wnt/β-catenin pathway is activated in prostate cancer after androgen deprivation, promoting androgen-independent growth.
• Inhibiting the Wnt/β-catenin pathway can re-sensitize CRPC cells to antiandrogen therapy.
• Combined inhibition of the Wnt/β-catenin pathway and AR signaling represents a promising therapeutic strategy for advanced prostate cancer.