Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo
Colon cancer is among the most common cancer types worldwide. Signaling pathways that control cell proliferation and migration play a crucial role in its progression. The G-protein-coupled protease-activated receptors (PARs) are associated mediators in this process. Both activated coagulation factor...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1631350/full |
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| author | Ulrike Meyer Ulrike Meyer Vincent Rönnpagel Sophie Grammbauer Mirjam von Lucadou Ursula Rauch-Kröhnert Edzard Schwedhelm Frank Dombrowski Christoph Ritter Bernhard H. Rauch Bernhard H. Rauch |
| author_facet | Ulrike Meyer Ulrike Meyer Vincent Rönnpagel Sophie Grammbauer Mirjam von Lucadou Ursula Rauch-Kröhnert Edzard Schwedhelm Frank Dombrowski Christoph Ritter Bernhard H. Rauch Bernhard H. Rauch |
| author_sort | Ulrike Meyer |
| collection | DOAJ |
| description | Colon cancer is among the most common cancer types worldwide. Signaling pathways that control cell proliferation and migration play a crucial role in its progression. The G-protein-coupled protease-activated receptors (PARs) are associated mediators in this process. Both activated coagulation factors thrombin and FXa are capable of activating PARs. While thrombin, beyond its intrinsic role in hemostasis, primarily activates PAR1, FXa mediates its cellular effects independently via PAR2. Although the role of thrombin and PAR1 activation in cancer development has been established for some time, the impact of FXa-PAR2 on tumor progression represents a relatively novel area of investigation. Therefore, the current study was conducted to examine the role of FXa and PAR2 signaling in colon cancer progression using the murine colon cancer cell line MC38. Proliferation and migration assays were performed in vitro and signaling pathways analyzed by Western blot. In vivo, tumor growth and health status were investigated in WT and PAR2-KO mice. The findings demonstrate that FXa considerably augments the proliferation and migration of colon cancer (CC) cells in vitro. A molecular mechanism of action has been identified in the activation of PAR2 by FXa. The coagulation factor significantly induces MAPK- and AKT-signaling with EGFR transactivation in the murine MC38 cells utilized. Although oral treatment with a direct FXa inhibitor (Apixaban) at a dosage of up to 50 mg/kg did not significantly affect tumor growth in vivo, PAR2 deficiency resulted in significantly reduced tumor growth and enhanced health condition status, indicating a key role of PAR2 in the progression of colon cancer. |
| format | Article |
| id | doaj-art-d4db4eec191d46eb92da894d93ce1a1f |
| institution | Kabale University |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-d4db4eec191d46eb92da894d93ce1a1f2025-08-20T03:51:19ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-07-011510.3389/fonc.2025.16313501631350Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivoUlrike Meyer0Ulrike Meyer1Vincent Rönnpagel2Sophie Grammbauer3Mirjam von Lucadou4Ursula Rauch-Kröhnert5Edzard Schwedhelm6Frank Dombrowski7Christoph Ritter8Bernhard H. Rauch9Bernhard H. Rauch10Pharmacology and Toxicology, University Medicine Oldenburg, Carl von Ossietzky Universität Oldenburg, Oldenburg, GermanyDepartment of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, Greifswald, GermanyDepartment of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, Greifswald, GermanyInstitute of Pathology, University Medicine Greifswald, Greifswald, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Eppendorf, Hamburg, GermanyDepartment of Cardiology, Angiology and Intensive Care, German Heart Center of Charité, Berlin, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Eppendorf, Hamburg, GermanyInstitute of Pathology, University Medicine Greifswald, Greifswald, GermanyDepartment of Clinical Pharmacy, Institute of Pharmacy, University Greifswald, Greifswald, GermanyPharmacology and Toxicology, University Medicine Oldenburg, Carl von Ossietzky Universität Oldenburg, Oldenburg, GermanyDepartment of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, Greifswald, GermanyColon cancer is among the most common cancer types worldwide. Signaling pathways that control cell proliferation and migration play a crucial role in its progression. The G-protein-coupled protease-activated receptors (PARs) are associated mediators in this process. Both activated coagulation factors thrombin and FXa are capable of activating PARs. While thrombin, beyond its intrinsic role in hemostasis, primarily activates PAR1, FXa mediates its cellular effects independently via PAR2. Although the role of thrombin and PAR1 activation in cancer development has been established for some time, the impact of FXa-PAR2 on tumor progression represents a relatively novel area of investigation. Therefore, the current study was conducted to examine the role of FXa and PAR2 signaling in colon cancer progression using the murine colon cancer cell line MC38. Proliferation and migration assays were performed in vitro and signaling pathways analyzed by Western blot. In vivo, tumor growth and health status were investigated in WT and PAR2-KO mice. The findings demonstrate that FXa considerably augments the proliferation and migration of colon cancer (CC) cells in vitro. A molecular mechanism of action has been identified in the activation of PAR2 by FXa. The coagulation factor significantly induces MAPK- and AKT-signaling with EGFR transactivation in the murine MC38 cells utilized. Although oral treatment with a direct FXa inhibitor (Apixaban) at a dosage of up to 50 mg/kg did not significantly affect tumor growth in vivo, PAR2 deficiency resulted in significantly reduced tumor growth and enhanced health condition status, indicating a key role of PAR2 in the progression of colon cancer.https://www.frontiersin.org/articles/10.3389/fonc.2025.1631350/fullmouse modelcolon cancerPAR2 in colon cancerFXa in colon cancerin vivo study |
| spellingShingle | Ulrike Meyer Ulrike Meyer Vincent Rönnpagel Sophie Grammbauer Mirjam von Lucadou Ursula Rauch-Kröhnert Edzard Schwedhelm Frank Dombrowski Christoph Ritter Bernhard H. Rauch Bernhard H. Rauch Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo Frontiers in Oncology mouse model colon cancer PAR2 in colon cancer FXa in colon cancer in vivo study |
| title | Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo |
| title_full | Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo |
| title_fullStr | Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo |
| title_full_unstemmed | Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo |
| title_short | Significance of FXa and its receptor PAR2 for the growth of colon cancer cells in vitro and in vivo |
| title_sort | significance of fxa and its receptor par2 for the growth of colon cancer cells in vitro and in vivo |
| topic | mouse model colon cancer PAR2 in colon cancer FXa in colon cancer in vivo study |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1631350/full |
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