Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• The Wnt/β-catenin pathway is upregulated in castration-resistant prostate cancer (CRPC).
• Polo-like kinase 1 (Plk1) is elevated in CRPC and inhibits tumor growth.
• The role of β-catenin pathway targeting in CRPC treatment is unclear.

Purpose of the Study:

• To investigate the regulatory role of Plk1 in Wnt/β-catenin signaling.
• To explore the therapeutic potential of targeting the Plk1-Wnt axis in CRPC.

Main Methods:

• Assessed β-catenin levels following Plk1 inhibition or depletion in prostate cancer cells.
• Evaluated the combined effect of Plk1 and Wnt/β-catenin pathway inhibitors on cancer cells and xenografts.
• Investigated the molecular mechanism involving axin2 as a Plk1 substrate.

Main Results:

• Plk1 inhibition increased cytosolic and nuclear β-catenin levels.
• Combined inhibition of Plk1 and Wnt/β-catenin pathways enhanced antineoplastic effects.
• Plk1 phosphorylates axin2, promoting β-catenin degradation and inhibiting axin2 degradation.

Conclusions:

• Plk1 acts as a negative regulator of the Wnt/β-catenin pathway in prostate cancer.
• A novel Plk1-Wnt signaling axis was identified.
• Targeting this axis presents a promising therapeutic strategy for CRPC.