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Open AccessArticle

Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients

1
Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The Netherlands
2
Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Campinas 13083-862, SP, Brazil
3
PlateInnove Biotechnology, 13414-018 Piracicaba, SP, Brazil
4
Department of Hematology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The Netherlands
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(7), 936; https://doi.org/10.3390/jcm8070936
Received: 16 May 2019 / Revised: 17 June 2019 / Accepted: 21 June 2019 / Published: 28 June 2019
(This article belongs to the Section Hematology)
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. View Full-Text
Keywords: platelet function; gastrointestinal cancer; venous thromboembolism; tyrosine phosphatases; LMWPTP; ACP1; PTP1B platelet function; gastrointestinal cancer; venous thromboembolism; tyrosine phosphatases; LMWPTP; ACP1; PTP1B
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Faria, A.V.S.; Andrade, S.S.; Reijm, A.N.; Spaander, M.C.W.; de Maat, M.P.M.; Peppelenbosch, M.P.; Ferreira-Halder, C.V.; Fuhler, G.M. Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients. J. Clin. Med. 2019, 8, 936.

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