Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner

Abstract

Advanced-stage prostate tumors metastasize to the bone, often causing death. The protein kinase D (PKD) family has been implicated in prostate cancer development; however, its role in prostate cancer metastasis remains elusive. This study examined the contribution of PKD, particularly PKD2 and PKD3 (PKD2/3), to the metastatic potential of prostate cancer cells and the effect of PKD inhibition on prostate cancer bone metastasis in vivo. Depletion of PKD2/3 by siRNAs or inhibition by the PKD inhibitor CRT0066101 in AR-positive and AR-negative castration-resistant prostate cancer cells potently inhibited colony formation and cell migration. Depletion or inhibition of PKD2/3 significantly blocked tumor cell invasion and suppressed the expression of genes related to bone metastasis in the highly invasive PC3-ML cells. The reduced invasive activity resulting from PKD2/3 depletion was in part mediated by the transcription factor Runx2, as its silencing decreased PKD2/3-mediated metastatic gene expression through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling axis. Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 plays an important role in the bone metastasis of prostate cancer cells, and its inhibition may be beneficial for the treatment of advanced prostate cancer.