2012年8月13日 訊 /生物谷BIOON/ --蛋白激酶D3（PKD3）雖然已被證明有助于前列腺癌細(xì)胞的生長(zhǎng)和生存,，但其在前列腺癌細(xì)胞運(yùn)動(dòng)中的作用仍不清楚,。
近日,，一項(xiàng)刊登在J Cell Sci雜志上的研究表明PKD2和PKD3激活核因子-κB（NF-κB）信號(hào)和促進(jìn)尿激酶型纖溶酶原激活因子（uPA）的表達(dá)/激活，而后兩者對(duì)前列腺癌細(xì)胞的侵襲是至關(guān)重要的,。
沉默內(nèi)源性PKD2或/和 PKD3的表達(dá)能顯著降低前列腺癌的細(xì)胞遷移和侵襲,，同時(shí)uPA和尿激酶受體（uPAR）的表達(dá)也會(huì)降低，但纖溶酶原激活物抑制劑（PAI-2）的表達(dá)會(huì)增加,。這些結(jié)果進(jìn)一步證實(shí)發(fā)現(xiàn)PKD2和PKD3促進(jìn)uPA和基質(zhì)金屬蛋白酶MMP-9的活性,。
此外，PKD2和/或PKD3表達(dá)被抑制后,， p65 NF-κB結(jié)合到尿激酶啟動(dòng)子的能力降低,，uPA的轉(zhuǎn)錄激活被抑制。內(nèi)源性PKD2和PKD3與IκB激酶β（IKKβ）相互作用,，PKD2主要調(diào)控PIKK-IκB的p65核易位以及p65的Ser276磷酸化，而PKD3主要調(diào)控P65的Ser536磷酸化,。相反,，恢復(fù)Ser536的磷酸化能逆轉(zhuǎn)PKD3沉默帶來的抑制uPA轉(zhuǎn)錄的功效，而恢復(fù)p65的異位表達(dá)也能逆轉(zhuǎn)PKD2或PKD3沉默后抑制腫瘤細(xì)胞侵襲的作用,。
有趣的是,，PKD3與組蛋白去乙酰化酶1（HDAC1）相互作用后能抑制HDAC1的表達(dá),，并降低其結(jié)合尿激酶啟動(dòng)子區(qū)域的能力,。此外，HDAC1的去除能導(dǎo)致敲除PKD3的細(xì)胞uPA轉(zhuǎn)錄恢復(fù)?？傊@些數(shù)據(jù)表明,，PKD2和PKD3相互作用通過p65的NF-κB和HDAC1介導(dǎo)的uPA表達(dá)和活化協(xié)同促進(jìn)前列腺癌細(xì)胞侵襲。（生物谷：Bioon.com）
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.
