LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites
LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites
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DOI：
10.1093/carcin/bgp011
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发表时间：
2009-03-01
期刊：
影响因子：
4.7
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Komachi, Mayumi;Tomura, Hideaki;Okajima, Fumikazu
据报道，胰腺癌患者的恶性腹水通过溶血磷脂酸(LPA)和LPA(1)受体刺激胰腺癌细胞的迁移。事实上，在PANC-1细胞中，LPA(1)和LPA(3)拮抗剂Ki16425可以抑制腹水和LPA诱导的迁移。然而，出乎意料的是，在Ki16425存在的情况下，腹水和LPA抑制了细胞对表皮生长因子(EGF)的迁移。在G(I)蛋白抑制剂百日咳毒素(PTX)处理的细胞中，也观察到对腹水和LPA的抑制迁移反应，并被LPA(2)受体特异性的小干扰RNA(SiRNA)减弱。这种抑制LPA的作用可被p115RhogenG蛋白信号域、显性负性RhoA或C3毒素所逆转。事实上，LPA激活了RhoA，而RhoA被针对LPA(2)受体的siRNA减弱。此外，LPA(2)激动剂LP-105也抑制了EGF诱导的PTX处理细胞的迁移。在YAPC-PD、BxPC-3、CFPAC-1和PK-1胰腺癌细胞系中也观察到类似的通过LPA(2)受体的抑制性迁移反应。在体外Matrigel侵袭实验中，LPA还抑制了PTX处理的PANC-1细胞的侵袭。我们认为LPA(2)受体与G(12/13)蛋白/Rho信号通路偶联，从而抑制EGF诱导的胰腺癌细胞的迁移和侵袭。
Malignant ascites from pancreatic cancer patients has been reported to stimulate migration of pancreatic cancer cells through lysophosphatidic acid (LPA) and LPA(1) receptors. Indeed, ascites- and LPA-induced migration was inhibited by Ki16425, an LPA(1) and LPA(3) antagonist, in Panc-1 cells. Unexpectedly, however, in the presence of Ki16425, ascites and LPA inhibited cell migration in response to epidermal growth factor (EGF). The inhibitory migratory response to ascites and LPA was also observed in the cells treated with pertussis toxin (PTX), a G(i) protein inhibitor, and attenuated by a small interfering RNA (siRNA) specific to the LPA(2) receptor. The inhibitory LPA action was reversed by the regulators of G-protein signaling domain of p115RhoGEF, dominant-negative RhoA or C3 toxin. Indeed, LPA activated RhoA, which was attenuated by the siRNA against the LPA(2) receptor. Moreover, LP-105, an LPA(2) agonist, also inhibited EGF-induced migration in the PTX-treated cells. A similar inhibitory migration response through LPA(2) receptors was also observed in YAPC-PD, BxPC-3, CFPAC-1 and PK-1 pancreatic cancer cell lines. LPA also inhibited the invasion of Panc-1 cells in the PTX-treated cells in the in vitro Matrigel invasion assay. We conclude that LPA(2) receptors are coupled to the G(12/13) protein/Rho-signaling pathway, leading to the inhibition of EGF-induced migration and invasion of pancreatic cancer cells.