蛋白激酶D（PKD）家族成员在前列腺癌（PC）中扮演着争议性的角色。因此，在进展期肿瘤中，PKD1几乎不存在，而PKD2和PKD3上调。此外，这些激酶激活对于PC进展的后果仍然大部分不清楚。因此，我们首次研究了PKD在PC细胞运动性方面的功能，并分析了潜在的分子机制。我们发现，在PKD抑制后，Snail水平明显下降，继而导致细胞迁移和侵袭受损，显示了PKD活性在调控PC进展中这一关键转录因子上的前所未有的作用。具体而言，我们展示了PKD2活性介导了MEK/ERK通路对Snail表达的影响，建立了ERK/PKD2/Snail级联在PC细胞侵袭调控中的共同功能。这些结果促使我们研究了PKD2和ERK活性与不同阶段PC患者样本中Snail丰度之间的相关性对临床相关性，并分析其对肿瘤预后和患者存活的影响。重要的是，这是第一项定义活性PKD2和Snail水平之间直接相关性的研究，进一步与ERK活性相关联。我们还证实PKD2活性与重要的不良预后因素相关。因此，表达模式为：活性PKD2高/活性ERK高/Snail高的PC患者表现出增加的浸润和转移，以及存活减少。我们的发现为了解参与PC进展的分子机制提供了新的见解，并确定了活性PKD2和Snail水平的组合与活性ERK的额外测量作为一种可靠的生物标志物来预测进展期PC患者的临床结果。版权所有 © 2023年 Elsevier B.V. 发布。

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.Copyright © 2023. Published by Elsevier B.V.