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首页> 外文期刊>Molecular cancer research: MCR >Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis.
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Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis.

机译：蛋白酶激活的受体（PAR1和PAR2）促进肿瘤细胞的运动和转移。

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The effects of the pleiotropic serine protease thrombin on tumor cells are commonly thought to be mediated by the thrombin receptor protease-activated receptor 1 (PAR1). We demonstrate here that PAR1 activation has a role in experimental metastasis using the anti-PAR1 antibodies ATAP2 and WEDE15, which block PAR1 cleavage and activation. Thrombin also stimulates chemokinesis of human melanoma cells toward fibroblast conditioned media and soluble matrix proteins. Thrombin-enhanced migration is abolished by anti-PAR1 antibodies, demonstrating that PAR1 cleavage and activation are required. The PAR1-specific agonist peptide TFLLRNPNDK, however, does not stimulate migration, indicating that PAR1 activation is not sufficient. In contrast, a combination of TFLLRNPNDK and the PAR2 agonist peptide SLIGRL mimics the thrombin effect on migration, whereas PAR2 agonist alone has no effect. Agonist peptides for the thrombin receptors PAR3 and PAR4 used alone or with PAR1 agonist also have no effect. Similarly, activation of PAR1 and PAR2 also enhances chemokinesis of prostate cancer cells. Desensitization with PAR2 agonist abolishes thrombin-enhanced cell motility, demonstrating that thrombin acts through PAR2. PAR2 is cleaved by proteases with trypsin-like specificity but not by thrombin. Thrombin enhances migration in the presence of a cleavage-blocking anti-PAR2 antibody, suggesting that thrombin activates PAR2 indirectly and independent of receptor cleavage. Treatment of melanoma cells with trypsin or PAR2 agonist peptide enhances experimental metastasis. Together, these data confirm a role for PAR1 in migration and metastasis and demonstrate an unexpected role for PAR2 in thrombin-dependent tumor cell migration and in metastasis.
机译：通常认为多效性丝氨酸蛋白酶凝血酶对肿瘤细胞的作用是由凝血酶受体蛋白酶激活受体1（PAR1）介导的。在这里，我们证明了PAR1激活在使用抗PAR1抗体ATAP2和WEDE15的实验性转移中发挥了作用，这可阻止PAR1的裂解和激活。凝血酶还刺激人黑素瘤细胞趋向于成纤维细胞条件培养基和可溶性基质蛋白。凝血酶增强的迁移被抗PAR1抗体消除，表明需要PAR1裂解和激活。但是，PAR1特异性激动剂肽TFLLRNPNDK不会刺激迁移，表明PAR1激活是不够的。相反，TFLLRNPNDK和PAR2激动剂肽SLIGRL的组合模拟了凝血酶对迁移的作用，而仅PAR2激动剂没有作用。单独使用或与PAR1激动剂一起使用的凝血酶受体PAR3和PAR4的激动剂肽也无效。同样，PAR1和PAR2的激活也可增强前列腺癌细胞的趋化作用。 PAR2激动剂引起的脱敏消除了凝血酶增强的细胞运动，表明凝血酶通过PAR2起作用。 PAR2被具有胰蛋白酶样特异性的蛋白酶切割，但不被凝血酶切割。凝血酶在裂解阻断型抗PAR2抗体的存在下增强迁移，这表明凝血酶可间接激活PAR2，而与受体裂解无关。用胰蛋白酶或PAR2激动剂肽治疗黑素瘤细胞可增强实验性转移。总之，这些数据证实了PAR1在迁移和转移中的作用，并证明了PAR2在凝血酶依赖性肿瘤细胞迁移和转移中出乎意料的作用。

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