Department of Biomedical Sciences, Dong-A University, Busan 49315, Korea.
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
Int J Mol Sci. 2022 Aug 24;23(17):9596. doi: 10.3390/ijms23179596.
Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.
与许多报道称抗血小板药物抑制癌症生长和转移相反，在接受长期抗血小板治疗的患者中已报告有新的实体肿瘤。我们研究了这些药物在没有血小板的情况下直接对癌细胞的影响，以模拟长期治疗的效果。当将四种抗血小板药物（阿司匹林、氯吡格雷、普拉格雷和替卡格雷）给予结肠癌细胞时，与先前的研究一样，癌细胞增殖受到抑制。然而，令人惊讶的是，当用嘌呤能 P2Y12 抑制剂（嘌呤类抗血小板药物）处理细胞时，癌细胞的迁移能力显著增加。因此，鉴定了基因表达谱以研究 P2Y12 抑制剂对细胞迁移的影响，发现 Serpin 家族 1（SERPINE1）是与三组细胞迁移和细胞死亡相关的共同基因。抗血小板治疗增加了癌细胞中 SERPINE1 的水平，并促进 SERPINE1 分泌到培养基中。发现增加的 SERPINE1 诱导 MMP1，从而增加细胞迁移。此外，还通过接受这些抗血小板药物的患者的血清证实了 SERPINE1 的增加。有了这些结果，我们提出 SERPINE1 可以作为一种新的靶基因，以预防长期抗血小板治疗患者中癌症的发生和转移。
