Lysophosphatidic acid induces MDA-MB-231 breast cancer cells migration through activation of PI3K/PAK1/ERK signaling.
Lysophosphatidic acid induces MDA-MB-231 breast cancer cells migration through activation of PI3K/PAK1/ERK signaling.
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溶血磷脂酸通过激活 PI3K/PAK1/ERK 信号传导诱导 MDA-MB-231 乳腺癌细胞迁移
DOI：
10.1371/journal.pone.0015940
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发表时间：
2010-12-30
期刊：
影响因子：
3.7
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Du J;Sun C;Hu Z;Yang Y;Zhu Y;Zheng D;Gu L;Lu X
增强癌细胞的运动性是促进肿瘤转移的关键步骤。溶血磷脂酸（LPA），代表血清中的主要促有丝分裂活性，刺激各种类型的癌细胞的迁移。然而，LPA诱导的癌细胞运动的潜在信号机制仍有待阐明。在这项研究中，我们发现LPA剂量依赖性地刺激MDA-MB-231乳腺癌细胞的迁移，10 μM是最有效的。MEK抑制剂U 0126可阻断LPA诱导的ERK活性和细胞迁移。此外，LPA诱导PAK 1活化，而ERK活化和细胞迁移被抑制在MDA-MB-231细胞中PAK 1的失活突变形式的异位表达。PI 3 K抑制剂LY 294002可抑制LPA诱导的PAK 1/ERK活化和细胞迁移。LPA处理乳腺癌细胞后，细胞内活性氧（ROS）大量产生，而ROS清除剂N-乙酰-L-半胱氨酸（N-acetyl-L-Cysteine）可抑制LPA诱导的ROS产生、PI 3 K/PAK 1/ERK激活和细胞迁移。总之，本研究确定了LPA刺激的乳腺癌细胞迁移的PI 3 K/PAK 1/ERK信号通路。这些数据还表明，ROS的产生在LPA刺激的PI 3 K/PAK 1/ERK信号转导和乳腺癌细胞迁移的激活中起着至关重要的作用。这些发现可能为设计未来阻断乳腺癌转移的治疗策略提供依据。
Enhanced motility of cancer cells is a critical step in promoting tumor metastasis. Lysophosphatidic acid (LPA), representing the major mitogenic activity in serum, stimulates migration in various types of cancer cells. However, the underlying signaling mechanisms for LPA-induced motility of cancer cells remain to be elucidated. In this study, we found that LPA dose-dependently stimulated migration of MDA-MB-231 breast cancer cells, with 10 µM being the most effective. LPA also increased ERK activity and the MEK inhibitor U0126 could block LPA-induced ERK activity and cell migration. In addition, LPA induced PAK1 activation while ERK activation and cell migration were inhibited by ectopic expression of an inactive mutant form of PAK1 in MDA-MB-231 cells. Furthermore, LPA increased PI3K activity, and the PI3K inhibitor LY294002 inhibited both LPA-induced PAK1/ERK activation and cell migration. Moreover, in the breast cancer cell, LPA treatment resulted in remarkable production of reactive oxygen species (ROS), while LPA-induced ROS generation, PI3K/PAK1/ERK activation and cell migration could be inhibited by N-acetyl-L-Cysteine, a scavenger of ROS. Taken together, this study identifies a PI3K/PAK1/ERK signaling pathway for LPA-stimulated breast cancer cell migration. These data also suggest that ROS generation plays an essential role in the activation of LPA-stimulated PI3K/PAK1/ERK signaling and breast cancer cell migration. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis.
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影响因子：
5.3
作者：
Manser, E;Huang, HY;Lim, L
通讯作者：
Lim, L
影响因子：
4.8
作者：
Cheng, Chunming;Kong, Xiangfei;Gu, Jianxin
通讯作者：
Gu, Jianxin
影响因子：
8
作者：
Huang, Q;Shen, HM;Ong, CN
通讯作者：
Ong, CN
影响因子：
4.8
作者：
Adam, L;Vadlamudi, R;Kumar, R
通讯作者：
Kumar, R
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela