Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells.
Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells.
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发表时间：
2001-08
期刊：
影响因子：
11.2
通讯作者：
Lakshmi Kamath;Ahou Meydani;F. Foss;A. Kuliopulos
中科院分区：
文献类型：
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作者：
Lakshmi Kamath;Ahou Meydani;F. Foss;A. Kuliopulos
蛋白水解酶赋予癌症一个决定性的特征，即能够突破细胞外基质屏障，并对趋化信号做出反应，侵入其他组织。近年来，细胞表面蛋白水解酶激活受体(PAR)-1被证明是炎症细胞中的趋化因子受体，其表达与乳腺癌细胞的转移倾向密切相关。本研究的目的是确定PAR1或其他已知的PAR2-4是否可以调节乳腺癌细胞的迁移和侵袭。我们发现，高侵袭性的MDAMB231乳腺癌细胞株表达非常高水平的功能性PAR1、PAR2和PAR4，而微侵袭性的MCF7细胞具有微量的PAR1和低水平的PAR2和PAR4。尽管PAR2和PAR4在表达上存在差异，但在侵袭性和微侵袭性乳腺细胞系中，PAR2和PAR4都是趋化因子受体。出乎意料的是，我们发现凝血酶或多肽激动剂SFLLRN激活PAR1显著抑制了MDAMB231细胞的侵袭和迁移，当应用于细胞运动方向的浓度梯度时。此外，我们还证明趋化作用的抑制是通过G(I)/磷脂酰肌醇-3-羟基激酶依赖的途径来实现的。肾上腺素或黄蜂毒马斯托瓦兰激活G(I)信号也抑制了乳腺癌细胞的侵袭和迁移。这些发现表明，针对乳腺癌细胞中选择性表达的G(I)偶联蛋白的治疗方法可能被证明对阻止浸润性乳腺癌的进展是有益的。
Proteases give cancer a defining characteristic of being able to break through extracellular matrix barriers and invade into other tissues in response to chemotactic signals. Recently, the cell surface protease-activated receptor (PAR)-1 has been shown to act as a chemokine receptor in inflammatory cells, and its expression is tightly correlated with metastatic propensity of breast cancer cells. The aim of the present study was to determine whether activation of PAR1 or the other known PARs (PAR2-4) can regulate migration and invasion of breast cancer cells. We found that the highly invasive MDAMB231 breast cancer cell line expressed very high levels of functional PAR1, PAR2, and PAR4, whereas minimally invasive MCF7 cells had trace amounts of PAR1 and low levels of PAR2 and PAR4. Despite the differences in expression, PAR2 and PAR4 acted as chemokine receptors in both invasive and minimally invasive breast cell lines. Quite unexpectedly, we found that activation of PAR1 with thrombin or the peptide agonist SFLLRN markedly inhibited invasion and migration of MDAMB231 cells when applied as a concentration gradient in the direction of cell movement. Additionally, we demonstrated that inhibition of chemotaxis was mediated through a G(i)/phosphoinositide-3-OH kinase-dependent pathway. Activation of G(i) signaling with epinephrine or wasp venom mastoparan also inhibited invasion and migration of the breast cancer cells. These findings suggest that therapeutics targeted toward G(i)-couplers that are selectively expressed in breast cancer cells could prove beneficial in halting the progression of invasive breast cancer.