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Secretory SERPINE1 Expression Is Increased by Antiplatelet Therapy, Inducing MMP1 Expression and Increasing Colon
Won-Tae Kim1, Jeong-Yeon Mun1, Seung-Woo Baek2,3
1Department of Biomedical Sciences, Dong-A University, Busan 49315, Korea.
Abstract:
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.
Insights
Long-term antiplatelet therapy may unexpectedly increase cancer cell motility by elevating SERPINE1 levels, potentially promoting metastasis. This suggests SERPINE1 as a novel therapeutic target for cancer prevention in patients on these medications.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Antiplatelet agents are widely used for cardiovascular disease prevention.
- Previous studies suggested antiplatelet agents inhibit cancer growth.
- However, new solid tumors have been reported in patients on long-term antiplatelet therapy.
Purpose of the Study:
- To investigate the direct effects of antiplatelet agents on cancer cells.
- To understand the mechanisms behind potential increased cancer cell motility.
- To identify novel therapeutic targets for cancer prevention in patients on antiplatelet therapy.
Main Methods:
- In vitro treatment of colon cancer cells with four antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor) and a purinergic P2Y12 inhibitor.
- Gene expression profiling to identify key genes involved in cell mobility.
- Measurement of SERPINE1 levels in cancer cells, cell culture medium, and patient serum.
Main Results:
- Antiplatelet agents inhibited cancer cell proliferation.
- A purinergic P2Y12 inhibitor significantly increased cancer cell motility.
- P2Y12 inhibition upregulated Serpin family 1 (SERPINE1) expression and secretion.
- Increased SERPINE1 induced MMP1, further promoting cell migration.
- Elevated SERPINE1 levels were confirmed in the serum of patients receiving antiplatelet drugs.
Conclusions:
- Long-term antiplatelet therapy, particularly via P2Y12 inhibition, may promote cancer cell metastasis.
- SERPINE1 is a key mediator of increased cancer cell motility induced by antiplatelet agents.
- SERPINE1 represents a potential therapeutic target to prevent cancer onset and metastasis in patients on long-term antiplatelet therapy.
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