J Cell Sci：蛋白激酶通过尿激酶促进前列腺癌侵袭转移

蛋白激酶D3（PKD3）虽然已被证明有助于前列腺癌细胞的生长和生存，但其在前列腺癌细胞运动中的作用仍不清楚。

近日，一项刊登在J Cell Sci杂志上的研究表明PKD2和PKD3激活核因子-κB（NF-κB）信号和促进尿激酶型纤溶酶原激活因子（uPA）的表达/激活，而后两者对前列腺癌细胞的侵袭是至关重要的。

沉默内源性PKD2或/和 PKD3的表达能显著降低前列腺癌的细胞迁移和侵袭，同时uPA和尿激酶受体（uPAR）的表达也会降低，但纤溶酶原激活物抑制剂（PAI-2）的表达会增加。这些结果进一步证实发现PKD2和PKD3促进uPA和基质金属蛋白酶MMP-9的活性。

此外，PKD2和/或PKD3表达被抑制后， p65 NF-κB结合到尿激酶启动子的能力降低，uPA的转录激活被抑制。内源性PKD2和PKD3与IκB激酶β（IKKβ）相互作用，PKD2主要调控PIKK-IκB的p65核易位以及p65的Ser276磷酸化，而​​PKD3主要调控P65的Ser536磷酸化。相反，恢复Ser536的磷酸化能逆转PKD3沉默带来的抑制uPA转录的功效，而恢复p65的异位表达也能逆转PKD2或PKD3沉默后抑制肿瘤细胞侵袭的作用。

有趣的是，PKD3与组蛋白去乙酰化酶1（HDAC1）相互作用后能抑制HDAC1的表达，并降低其结合尿激酶启动子区域的能力。此外，HDAC1的去除能导致敲除PKD3的细胞uPA转录恢复。总之这些数据表明，PKD2和PKD3相互作用通过p65的NF-κB和HDAC1介导的uPA表达和活化协同促进前列腺癌细胞侵袭。

doi:10.1242/jcs.106542
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PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1.

Zou Z, Zeng F, Xu W, Wang C, Ke Z, Wang QJ, Deng F.

Although protein kinase D3 (PKD3) has been shown to contribute to prostate cancer cell growth and survival, the role of PKD in prostate cancer cell motility remains unclear. Here, we show that PKD2 and PKD3 promote nuclear factor-kappaB (NF-κB) signaling and urokinase-type plasminogen activator (uPA) expression/activation, which are critical to prostate cancer cell invasion. Silencing of endogenous PKD2 and/or PKD3 markedly decreased prostate cancer cell migration and invasion, reduced uPA and uPA receptor (uPAR) expression, and increased plasminogen activator inhibitor-2 (PAI-2) expression. These results were further substantiated by the finding that PKD2 and PKD3 promoted the activity of uPA and matrix metalloproteinase (MMP)-9. Furthermore, depletion of PKD2 and/or PKD3 decreased the binding of p65 NF-κB to the uPA promoter, suppressing transcriptional activation of uPA. Endogenous PKD2 and PKD3 interacted with IκB kinase β (IKKβ); PKD2 mainly regulated the pIKK-IκB-p65 nuclear translocation cascade and phosphorylation of Ser276 on p65, while PKD3 was responsible for the phosphorylation of Ser536 on p65. Conversely, inhibition of uPA transactivation by PKD3 silencing was rescued by constitutive Ser536 phosphorylation, and reduced tumor cell invasion resulting from PKD2 or PKD3 silencing was rescued by ectopic expression of p65. Interestingly, PKD3 interacted with histone deacetylase 1 (HDAC1), suppressing HDAC1 expression and decreasing its binding to the uPA promoter. Moreover, depletion of HDAC1 resulted in recovery of uPA transactivation in PKD3-knockdown cells. Taken together, these data suggest that PKD2 and PKD3 may coordinate to promote prostate cancer cell invasion through p65 NF-κB- and HDAC1-mediated expression and activation of uPA.