Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Prostate cancer metastasis is a leading cause of cancer-related mortality in men.
• The precise regulation of protein kinase D3 (PKD3), a facilitator of tumor growth and metastasis, remains largely unknown.
• Heat shock protein 90 (Hsp90) is a chaperone protein that stabilizes signaling client proteins, contributing to the malignant phenotype.

Purpose of the Study:

• To investigate the role of Hsp90 in regulating PKD3 stability and function in prostate cancer.
• To elucidate the mechanism by which Hsp90 influences prostate cancer cell migration.
• To identify PKD3 as a potential client protein of Hsp90.

Main Methods:

• Utilized various prostate cancer cell lines (DU145, PC3, LNCaP).
• Employed pharmacological inhibition of PKDs and Hsp90 (ganetespib).
• Performed proximity ligation assays, immunoprecipitation, and siRNA knockdown experiments.

Main Results:

• Hsp90 inhibition abrogated prostate cancer cell migration in a dose-dependent manner.
• Ganetespib treatment led to the depletion of PKD2, PKD3, and Akt.
• Demonstrated a direct physical interaction between Hsp90 and PKD3, leading to PKD3 misfolding and degradation upon inhibition.
• PKD3 knockdown combined with Hsp90 inhibition confirmed PKD3's specific role in cell migration, dependent on Hsp90.

Conclusions:

• Identified PKD3 as a client protein of Hsp90 in prostate cancer.
• Uncovered a novel mechanism involving Hsp90-mediated stabilization of PKD3 in promoting prostate cancer metastasis.
• The Hsp90-PKD3 interaction presents a potential therapeutic vulnerability for targeting prostate cancer progression.