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.
