Protein Kinase D1 Inhibits Cell Proliferation through Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Secretion in Prostate Cancer
Protein Kinase D1 Inhibits Cell Proliferation through Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Secretion in Prostate Cancer
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DOI：
10.1158/0008-5472.can-09-4155
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发表时间：
2010-03-01
期刊：
影响因子：
11.2
通讯作者：
Balaji, K. C.
中科院分区：
文献类型：
--
作者：
Biswas, M. Helal Uddin;Du, Cheng;Balaji, K. C.
我们和其他人之前表明，蛋白激酶 D1 (PKD1) 在包括前列腺癌在内的多种癌症中表达下调。与 E-钙粘蛋白（一种主要细胞粘附上皮蛋白）相互作用；并导致前列腺癌细胞的细胞聚集增加和运动性降低。在这项研究中，我们发现 PKD1 与 β 3-整合素复合，导致丝裂原激活蛋白激酶/细胞外信号调节激酶 (ERK) 激酶-ERK 通路的激活，从而导致基质金属蛋白酶 (MMP)-2 和 MMP-9 的产生增加，这与可溶性 80 kDa E-钙粘蛋白胞外结构域的脱落有关。有趣的是，MMP-2 和 MMP-9 抑制剂可以挽救 PKD1 转染后细胞增殖的减少，并通过重组 MMP-2 (rMMP-2) 和 rMMP-9 蛋白增强，这表明 MMP 在前列腺癌中具有抗增殖作用。对公开可用的 DNA 微阵列数据集进行的计算机分析转化研究表明，人前列腺组织中 PKD1 和 MMP-2 表达之间存在显着的直接相关性。该研究显示了 PKD1 抗增殖作用的新机制，PKD1 是一种在多种人类癌症中新兴的翻译兴趣蛋白，通过增加癌细胞中 MMP-2 和 MMP-9 的产生。癌症研究； 70(5)； 2095-104。 (C) 2010 AACR。
We and others previously showed that protein kinase D1 (PKD1) is downregulated in several cancers including prostate; interacts with E-cadherin, a major cell adhesion epithelial protein; and causes increased cell aggregation and decreased motility of prostate cancer cells. In this study, we show that PKD1 complexes with beta 3-integrin, resulting in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase-ERK pathway, which causes increased production of matrix metalloproteinase (MMP)-2 and MMP-9, that is associated with shedding of soluble 80 kDa E-cadherin extracellular domain. Interestingly, decreased cell proliferation following PKD1 transfection was rescued by MMP-2 and MMP-9 inhibitors and augmented by recombinant MMP-2 (rMMP-2) and rMMP-9 proteins, suggesting an antiproliferative role for MMPs in prostate cancer. Translational studies by in silico analysis of publicly available DNA microarray data sets show a significant direct correlation between PKD1 and MMP-2 expression in human prostate tissues. The study shows a novel mechanism for antiproliferative effects of PKD1, a protein of emerging translational interest in several human cancers, through increased production of MMP-2 and MMP-9 in cancer cells. Cancer Res; 70(5); 2095-104. (C) 2010 AACR.