Pharmacological Inhibition of Platelet-Tumor Cell Cross-Talk Prevents Platelet-Induced Overexpression of Cyclooxygenase-2 in HT29 Human Colon Carcinoma Cells
Pharmacological Inhibition of Platelet-Tumor Cell Cross-Talk Prevents Platelet-Induced Overexpression of Cyclooxygenase-2 in HT29 Human Colon Carcinoma Cells
复制标题
DOI：
10.1124/mol.113.084988
复制
发表时间：
2013-07-01
影响因子：
3.6
通讯作者：
Patrignani, Paola
中科院分区：
文献类型：
--
作者：
Dovizio, Melania;Maier, Thorsten J.;Patrignani, Paola
环氧合酶（考克斯）-2-衍生的前列腺素类可以影响几个与致癌相关的过程。我们的目的是解决这一假设，即血小板有助于异常考克斯-2在HT 29结肠癌细胞的表达，并揭示血小板诱导的考克斯-2的恶性肿瘤和上皮间质转化（EMT）的标志基因的蛋白质的表达的作用。与HT 29细胞共培养的人血小板迅速粘附于癌细胞并诱导考克斯-2 mRNA表达，但不诱导蛋白质合成，这需要血小板衍生生长因子的晚期释放和考克斯-2 mRNA的稳定。HT 29细胞中血小板诱导的考克斯-2依赖性前列腺素E-2（PGE（2））合成参与了p21（WAF 1/CIP 1）的下调和细胞周期蛋白B 1的上调，因为这些作用被罗非昔布（一种选择性考克斯-2抑制剂）阻止，并被外源性PGE（2）拯救。在HT 29细胞中高度表达的半乳糖凝集素-3在半乳糖凝集素中是独特的，因为它含有胶原样结构域。因此，我们研究了半乳糖凝集素3和血小板胶原受体在血小板诱导的考克斯-2过表达中的作用。半乳糖凝集素-3功能抑制剂（β-乳糖，半乳糖凝集素-3的显性阴性形式，Gal-3C和抗半乳糖凝集素-3抗体M3/38）或胶原受体介导的血小板粘附抑制剂（revacept，二聚体血小板胶原受体GPVI-Fc）可预防异常考克斯-2表达。在预防血小板诱导的EMT标志物的mRNA变化方面，瑞伐西普对血小板-癌细胞相互作用的抑制比罗非昔布更有效，这表明直接细胞-细胞接触和异常考克斯-2表达协同诱导与EMT相关的基因表达修饰。总之，我们的研究结果提供了在动物模型中测试胶原结合位点阻断剂（如revacept）和半乳糖凝集素-3抑制剂预防结肠癌转移的基本原理，然后在患者中进行研究。
Cyclooxygenase (COX)-2-derived prostanoids can influence several processes that are linked to carcinogenesis. We aimed to address the hypothesis that platelets contribute to aberrant COX-2 expression in HT29 colon carcinoma cells and to reveal the role of platelet-induced COX-2 on the expression of proteins involved in malignancy and marker genes of epithelial-mesenchymal transition (EMT). Human platelets cocultured with HT29 cells rapidly adhered to cancer cells and induced COX-2 mRNA expression, but not protein synthesis, which required the late release of platelet-derived growth factor and COX-2 mRNA stabilization. Platelet-induced COX-2-dependent prostaglandin E-2 (PGE(2)) synthesis in HT29 cells was involved in the down-regulation of p21(WAF1/CIP1) and the upregulation of cyclinB1 since these effects were prevented by rofecoxib (a selective COX-2 inhibitor) and rescued by exogenous PGE(2). Galectin-3, which is highly expressed in HT29 cells, is unique among galectins because it contains a collagen-like domain. Thus, we studied the role of galectin-3 and platelet collagen receptors in platelet-induced COX-2 overexpression. Inhibitors of galectin-3 function (beta-lactose, a dominant-negative form of galectin-3, Gal-3C, and anti-galectin-3 antibody M3/38) or collagen receptor-mediated platelet adhesion (revacept, a dimeric platelet collagen receptor GPVI-Fc) prevented aberrant COX-2 expression. Inhibition of platelet-cancer cell interaction by revacept was more effective than rofecoxib in preventing platelet-induced mRNA changes of EMT markers, suggesting that direct cell-cell contact and aberrant COX-2 expression synergistically induced gene expression modifications associated with EMT. In conclusion, our findings provide the rationale for testing blockers of collagen binding sites, such as revacept, and galectin-3 inhibitors in the prevention of colon cancer metastasis in animal models, followed by studies in patients.