Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients
Venous thromboembolism (VTE) is one of the most common causes of cancer related mortality. It has been speculated that hypercoagulation in cancer patients is triggered by direct or indirect contact of platelets with tumor cells, however the underlying molecular mechanisms involved are currently unkn...
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doaj-a0571050e6914a579e64d814ad6264392020-11-25T00:32:01ZengMDPI AGJournal of Clinical Medicine2077-03832019-06-018793610.3390/jcm8070936jcm8070936Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer PatientsAlessandra V. S. Faria0Sheila S. Andrade1Agnes N. Reijm2Manon C. W. Spaander3Moniek P. M. de Maat4Maikel P. Peppelenbosch5Carmen V. Ferreira-Halder6Gwenny M. Fuhler7Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The NetherlandsPlateInnove Biotechnology, 13414-018 Piracicaba, SP, BrazilDepartment of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The NetherlandsDepartment of Hematology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The NetherlandsDepartment of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas 13083-862, SP, BrazilDepartment of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The NetherlandsVenous thromboembolism (VTE) is one of the most common causes of cancer related mortality. It has been speculated that hypercoagulation in cancer patients is triggered by direct or indirect contact of platelets with tumor cells, however the underlying molecular mechanisms involved are currently unknown. Unraveling these mechanisms may provide potential avenues for preventing platelet-tumor cell aggregation. Here, we investigated the role of protein tyrosine phosphatases in the functionality of platelets in both healthy individuals and patients with gastrointestinal cancer, and determined their use as a target to inhibit platelet hyperactivity. This is the first study to demonstrate that platelet agonists selectively activate low molecular weight protein tyrosine phosphatase (LMWPTP) and PTP1B, resulting in activation of Src, a tyrosine kinase known to contribute to several platelet functions. Furthermore, we demonstrate that these phosphatases are a target for 3-bromopyruvate (3-BP), a lactic acid analog currently investigated for its use in the treatment of various metabolic tumors. Our data indicate that 3-BP reduces Src activity, platelet aggregation, expression of platelet activation makers and platelet-tumor cell interaction. Thus, in addition to its anti-carcinogenic effects, 3-BP may also be effective in preventing platelet-tumor cell aggregationin cancer patients and therefore may reduce cancer mortality by limiting VTE in patients.https://www.mdpi.com/2077-0383/8/7/936platelet functiongastrointestinal cancervenous thromboembolismtyrosine phosphatasesLMWPTPACP1PTP1B |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alessandra V. S. Faria Sheila S. Andrade Agnes N. Reijm Manon C. W. Spaander Moniek P. M. de Maat Maikel P. Peppelenbosch Carmen V. Ferreira-Halder Gwenny M. Fuhler |
spellingShingle |
Alessandra V. S. Faria Sheila S. Andrade Agnes N. Reijm Manon C. W. Spaander Moniek P. M. de Maat Maikel P. Peppelenbosch Carmen V. Ferreira-Halder Gwenny M. Fuhler Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients Journal of Clinical Medicine platelet function gastrointestinal cancer venous thromboembolism tyrosine phosphatases LMWPTP ACP1 PTP1B |
author_facet |
Alessandra V. S. Faria Sheila S. Andrade Agnes N. Reijm Manon C. W. Spaander Moniek P. M. de Maat Maikel P. Peppelenbosch Carmen V. Ferreira-Halder Gwenny M. Fuhler |
author_sort |
Alessandra V. S. Faria |
title |
Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients |
title_short |
Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients |
title_full |
Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients |
title_fullStr |
Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients |
title_full_unstemmed |
Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients |
title_sort |
targeting tyrosine phosphatases by 3-bromopyruvate overcomes hyperactivation of platelets from gastrointestinal cancer patients |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2019-06-01 |
description |
Venous thromboembolism (VTE) is one of the most common causes of cancer related mortality. It has been speculated that hypercoagulation in cancer patients is triggered by direct or indirect contact of platelets with tumor cells, however the underlying molecular mechanisms involved are currently unknown. Unraveling these mechanisms may provide potential avenues for preventing platelet-tumor cell aggregation. Here, we investigated the role of protein tyrosine phosphatases in the functionality of platelets in both healthy individuals and patients with gastrointestinal cancer, and determined their use as a target to inhibit platelet hyperactivity. This is the first study to demonstrate that platelet agonists selectively activate low molecular weight protein tyrosine phosphatase (LMWPTP) and PTP1B, resulting in activation of Src, a tyrosine kinase known to contribute to several platelet functions. Furthermore, we demonstrate that these phosphatases are a target for 3-bromopyruvate (3-BP), a lactic acid analog currently investigated for its use in the treatment of various metabolic tumors. Our data indicate that 3-BP reduces Src activity, platelet aggregation, expression of platelet activation makers and platelet-tumor cell interaction. Thus, in addition to its anti-carcinogenic effects, 3-BP may also be effective in preventing platelet-tumor cell aggregationin cancer patients and therefore may reduce cancer mortality by limiting VTE in patients. |
topic |
platelet function gastrointestinal cancer venous thromboembolism tyrosine phosphatases LMWPTP ACP1 PTP1B |
url |
https://www.mdpi.com/2077-0383/8/7/936 |
work_keys_str_mv |
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