Protein kinase D activity is a risk biomarker in prostate cancer that drives cell invasion by a Snail/ERK dependent mechanism

Abstract

Protein kinase D (PKD) family members play controversial roles in prostate cancer (PC). Thus, PKD1 is nearly absent in advanced tumours, where PKD2 and PKD3 are upregulated. Additionally, consequences of activation of these kinases on PC progression remain largely unclear. Here, we first investigated PKD function on PC cell motility, analysing the underlying molecular mechanisms. We find a striking decrease of Snail levels after PKD inhibition followed by cell migration and invasion impairment, demonstrating an unprecedented role of PKD activity on the regulation of this key transcription factor in PC progression. Specifically, we show that PKD2 activity mediates the effects of MEK/ERK pathway on Snail expression, establishing a joint function of ERK/PKD2/Snail cascade in PC cell invasion regulation. These results led us to address the clinical relevance of the correlation between PKD2 and ERK activities with Snail abundance in samples from PC patients at different stages, analysing its impact on tumour prognosis and patients´ survival. Importantly, this is the first study defining a direct correlation between active PKD2 and Snail levels, further linked to ERK activity. We also evidence that PKD2 activity is associated with important poor prognostic factors. Thus, PC patients with the expression pattern: active PKD2high/active ERKhigh/Snailhigh exhibit increased invasiveness and metastasis, and decreased survival. Our findings provide new insights for understanding the molecular mechanisms involved in PC progression, pinpointing the combination of active PKD2 and Snail levels, with the additional measurement of active ERK, as a confident biomarker to predict clinical outcome of patients with advanced PC.