Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion.
Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion.
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DOI：
10.1186/1471-2407-14-208
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发表时间：
2014-03-19
期刊：
影响因子：
3.8
通讯作者：
Gee SH
中科院分区：
文献类型：
--
作者：
Cai K;Mulatz K;Ard R;Nguyen T;Gee SH
解开负责在癌细胞中建立转移表型的信号通路对于理解癌症的病理学是至关重要的。细胞运动性的获得是转移性肿瘤细胞的关键特性，并且是侵袭的先决条件。Rho GTP酶调节肌动蛋白细胞骨架重组和细胞运动和侵袭所需的细胞反应。二酰基甘油激酶β（DGK β）是一种磷酸化二酰基甘油产生磷脂酸的酶，调节Rho GTP酶Rac 1和RhoA的活性。DGKmRNA在几种不同的结肠癌细胞系中以及相对于正常结肠上皮的结肠癌组织中高度表达，因此可能有助于转移过程。为了研究DGK β在癌症转移中的潜在作用，使用人结肠直肠癌转移转化的细胞、同基因模型。在非转移性SW 480腺癌细胞系及其高转移性变体SW 620细胞系中测量DGK β蛋白水平、Rac 1和RhoA活性以及PAK磷酸化。在SW 620细胞中研究了DGK沉默对Rho GT3活性和通过Matrigel包被的Transwell插入物的侵袭的影响。还在消耗DGK β的PC-3前列腺癌和MDA-MB-231乳腺癌细胞中测量了侵袭性。与SW 480细胞相比，SW 620细胞中DGK β蛋白水平升高约3倍。SW 620细胞中活性Rac 1的增加，以及Rac 1效应物PAK 1的表达和磷酸化的显著增加。同样，SW 620细胞中RhoA活性和表达也增加。通过shRNA介导的沉默来敲低SW 620细胞中DGK β的表达显著降低了Rac 1和RhoA的活性，并减弱了SW 620细胞的体外侵袭力。在高转移性MDA-MB-231乳腺癌细胞和PC-3前列腺癌细胞中的DGK沉默也显著减弱了它们的侵袭性。升高的DGK β表达有助于增加Rho GT3活化和增强转移性癌细胞的运动性。这些发现保证了进一步研究结肠癌和其他癌症中DGK β上调的临床相关性。干扰DGKζ功能可以提供抑制侵袭和转移的手段。
Unraveling the signaling pathways responsible for the establishment of a metastatic phenotype in carcinoma cells is critically important for understanding the pathology of cancer. The acquisition of cell motility is a key property of metastatic tumor cells and is a prerequisite for invasion. Rho GTPases regulate actin cytoskeleton reorganization and the cellular responses required for cell motility and invasion. Diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates diacylglycerol to yield phosphatidic acid, regulates the activity of the Rho GTPases Rac1 and RhoA. DGKζ mRNA is highly expressed in several different colon cancer cell lines, as well as in colon cancer tissue relative to normal colonic epithelium, and thus may contribute to the metastatic process. To investigate potential roles of DGKζ in cancer metastasis, a cellular, isogenic model of human colorectal cancer metastatic transition was used. DGKζ protein levels, Rac1 and RhoA activity, and PAK phosphorylation were measured in the non-metastatic SW480 adenocarcinoma cell line and its highly metastatic variant, the SW620 line. The effect of DGKζ silencing on Rho GTPase activity and invasion through Matrigel-coated Transwell inserts was studied in SW620 cells. Invasiveness was also measured in PC-3 prostate cancer and MDA-MB-231 breast cancer cells depleted of DGKζ. DGKζ protein levels were elevated approximately 3-fold in SW620 cells compared to SW480 cells. There was a concomitant increase in active Rac1 in SW620 cells, as well as substantial increases in the expression and phosphorylation of the Rac1 effector PAK1. Similarly, RhoA activity and expression were increased in SW620 cells. Knockdown of DGKζ expression in SW620 cells by shRNA-mediated silencing significantly reduced Rac1 and RhoA activity and attenuated the invasiveness of SW620 cells in vitro. DGKζ silencing in highly metastatic MDA-MB-231 breast cancer cells and PC-3 prostate cancer cells also significantly attenuated their invasiveness. Elevated DGKζ expression contributes to increased Rho GTPase activation and the enhanced motility of metastatic cancer cells. These findings warrant further investigation of the clinical relevance of DGKζ upregulation in colon and other cancers. Interfering with DGKζ function could provide a means of inhibiting invasion and metastasis.
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影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO
DOI：
10.1073/pnas.0908326107
发表时间：
2010-03-02
影响因子：
11.1
作者：
Chianale, Federica;Rainero, Elena;Graziani, Andrea
通讯作者：
Graziani, Andrea
影响因子：
64.8
作者：
Barretina, Jordi;Caponigro, Giordano;Stransky, Nicolas;Venkatesan, Kavitha;Margolin, Adam A.;Kim, Sungjoon;Wilson, Christopher J.;Lehar, Joseph;Kryukov, Gregory V.;Sonkin, Dmitriy;Reddy, Anupama;Liu, Manway;Murray, Lauren;Berger, Michael F.;Monahan, John E.;Morais, Paula;Meltzer, Jodi;Korejwa, Adam;Jane-Valbuena, Judit;Mapa, Felipa A.;Thibault, Joseph;Bric-Furlong, Eva;Raman, Pichai;Shipway, Aaron;Engels, Ingo H.;Cheng, Jill;Yu, Guoying K.;Yu, Jianjun;Aspesi, Peter, Jr.;de Silva, Melanie;Jagtap, Kalpana;Jones, Michael D.;Wang, Li;Hatton, Charles;Palescandolo, Emanuele;Gupta, Supriya;Mahan, Scott;Sougnez, Carrie;Onofrio, Robert C.;Liefeld, Ted;MacConaill, Laura;Winckler, Wendy;Reich, Michael;Li, Nanxin;Mesirov, Jill P.;Gabriel, Stacey B.;Getz, Gad;Ardlie, Kristin;Chan, Vivien;Myer, Vic E.;Weber, Barbara L.;Porter, Jeff;Warmuth, Markus;Finan, Peter;Harris, Jennifer L.;Meyerson, Matthew;Golub, Todd R.;Morrissey, Michael P.;Sellers, William R.;Schlegel, Robert;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
3.3
作者：
Chianale, Federica;Cutrupi, Santina;Graziani, Andrea
通讯作者：
Graziani, Andrea
影响因子：
21.3
作者：
Kawasaki, Y;Sato, R;Akiyama, T
通讯作者：
Akiyama, T