Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates
tumor growth and
metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client
proteins, thus is an enabler of the malignant phenotype. Here, using different
prostate cancer cell lines, we report that Hsp90 ensures PKD3 conformational stability and function to promote
cancer cell migration. We found that pharmacological inhibition of either PKDs or Hsp90 dose-dependently abrogated the migration of DU145 and PC3 metastatic
prostate cancer cells. Hsp90 inhibition by
ganetespib caused a dose-dependent depletion of PKD2, PKD3, and Akt, which are all involved in
metastasis formation. Proximity
ligation assay and immunoprecipitation experiments demonstrated a physical interaction between Hsp90 and PKD3. Inhibition of the chaperone-client interaction induced misfolding and proteasomal degradation of PKD3. PKD3
siRNA combined with
ganetespib treatment demonstrated a specific involvement of PKD3 in DU145 and PC3 cell migration, which was entirely dependent on Hsp90. Finally, ectopic expression of PKD3 enhanced migration of non-metastatic LNCaP cells in an Hsp90-dependent manner. Altogether, our findings identify PKD3 as an Hsp90 client and uncover a potential mechanism of Hsp90 in
prostate cancer metastasis. The molecular interaction revealed here may regulate other
biological and pathological functions.