Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion.
Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion.
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DOI：
10.1038/sj.bjc.6605154
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发表时间：
2009-07-21
影响因子：
8.8
通讯作者：
Fu, S. B.
中科院分区：
文献类型：
--
作者：
Meng, X. N.;Jin, Y.;Yu, Y.;Bai, J.;Liu, G. Y.;Zhu, J.;Zhao, Y. Z.;Wang, Z.;Chen, F.;Lee, K-Y;Fu, S. B.
粘着斑激酶（FAK）在多种癌症中过表达，如乳腺癌、结肠癌、前列腺癌、卵巢癌和肺癌。然而，细胞外基质纤连蛋白通过FAK刺激肺癌细胞迁移和侵袭的机制仍有待研究。用蛋白质印迹法检测纤连蛋白介导的肺癌细胞迁移和侵袭的信号通路。通过伤口愈合、迁移和侵袭实验检测细胞的转移功能。此外，还使用RNA干扰和激酶抑制剂来研究下游信号。在这项研究中，我们研究了FAK信号通路与calpain-2和RhoA在纤连蛋白介导的肺癌细胞迁移和侵袭。我们发现纤连蛋白刺激的A549肺上皮细胞显示FAK及其下游靶点Src、ERK 1/2、磷脂酰肌醇3′-激酶（PI 3 K）和Akt的磷酸化增加。与该观察结果一致，通过siRNA消耗FAK导致Src、ERK 1/2、PI 3 K和Akt活性的抑制。此外，Src抑制剂PP 2阻断FAK、ERK 1/2、PI 3 K和Akt的磷酸化。相反，使用PD 98059抑制MEK 1/2降低了基质金属蛋白酶9（MMP 9）和钙蛋白酶2的表达。PI 3 K抑制剂LY 294002进一步阻断MMP 9和RhoA的表达。MEK 1/2和PI 3 K的抑制导致细胞迁移和侵袭减少。我们的数据表明，纤连蛋白介导的FAK激活，导致肺癌转移可能发生通过ERK或PI 3 K/Akt调节MMP 9/calpain-2或MMP 9/RhoA活性，分别。
Focal adhesion kinase (FAK) is overexpressed in a variety of cancers, such as breast, colon, prostate, ovary, and lung cancers. However, the mechanism by which extracellular matrix fibronectin stimulates lung cancer cell migration and invasion through FAK remains to be investigated. The signalling pathways in fibronectin-mediated lung cancer cell migration and invasion were examined using western blotting. The metastasis function was detected by wound healing, migration and invasion assays. Further, RNA interference and kinase inhibitors were also used to study the downstream signals. In this study, we examined the FAK signalling pathways in relation to calpain-2 and RhoA in fibronectin-mediated lung cancer cell migration and invasion. We found that A549 lung epithelial cells stimulated by fibronectin showed increased phosphorylation of FAK and its downstream targets, Src, ERK1/2, phosphatidylinositol 3′-kinase (PI3K), and Akt. Consistent with this observation, depletion of FAK by siRNA resulted in the inhibition of Src, ERK1/2, PI3K, and Akt activity. In addition, the Src inhibitor, PP2, blocked the phosphorylation of FAK, ERK1/2, PI3K, and Akt. Conversely, inhibition of MEK1/2 using PD98059 reduced the expression of matrix metalloproteinase-9 (MMP9) and calpain-2. The PI3K inhibitor, LY294002, further blocked the expression of MMP9 and RhoA. Inhibition of both MEK1/2 and PI3K caused reduced cell migration and invasion. Our data suggest that fibronectin-mediated activation of FAK that leads to lung cancer metastasis could occur through ERK or PI3K/Akt regulation of MMP9/calpain-2 or MMP9/RhoA activity, respectively.
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局灶性粘附激酶的激活通过细胞外信号调节的激酶-1/2信号传导途径激活来增强胰腺癌细胞的粘附和侵袭。
影响因子：
37.3
作者：
Sawai, Hirozumi;Okada, Yuji;Funahashi, Hitoshi;Matsuo, Yoichi;Takahashi, Hiroki;Takeyama, Hiromitsu;Manabe, Tadao
通讯作者：
Manabe, Tadao
影响因子：
4.8
作者：
Glading, A;Chang, P;Wells, A
通讯作者：
Wells, A
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
4.8
作者：
Chen, HC;Appeddu, PA;Guan, JL
通讯作者：
Guan, JL
DOI：
10.1111/j.1582-4934.2005.tb00364.x
发表时间：
2005-04-01
影响因子：
5.3
作者：
Mukhopadhyay, NK;Gordon, GJ;Jaklitsch, MT
通讯作者：
Jaklitsch, MT