Platelets induce free and phospholipid-esterified 12-hydroxyeicosatetraenoic acid generation in colon cancer cells by delivering 12-lipoxygenase

Contursi, A ; Schiavone, S ; Dovizio, M ; Hinz, C ; Fullone, R ; Tacconelli, S ; Tyrrell, VJ ; Grande, R ; Lanuti, P ; Marchisio, M ; Zucchelli, M ; Ballerini, P ; Lanas Arbelola, A (Universidad de Zaragoza) ; O''Donnell, VB ; Patrignani, P

Resumen: Platelets promote tumor metastasis by inducing promalignant phenotypes in cancer cells and directly contributing to cancer-related throm-botic complications. Platelet-derived extracellular vesicles (EVs) can promote epithelial-mesenchymal transition (EMT) in cancer cells, which confers high-grade malignancy. 12S-hydroxyeicosatetraenoic acid (12-HETE) generated by platelet-type 12-lipoxygenase (12-LOX) is considered a key modulator of cancer metastasis through unknown mechanisms. In plate-lets, 12-HETE can be esterified into plasma membrane phospholipids (PLs), which drive thrombosis. Using cocultures of human platelets and human colon adenocarcinoma cells (line HT29) and LC-MS/MS, we investigated the impact of platelets on cancer cell biosynthesis of 12S-HETE and its esterification into PLs and whether platelet ability to transfer its mo-lecular cargo might play a role. To this aim, we performed coculture experiments with CFSE[5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester]-loaded platelets. HT29 cells did not generate 12S-HETE or express 12-LOX. However, they ac-quired the capacity to produce 12S-HETE mainly esterified in plasmalogen phospholipid forms following the uptake of platelet-derived medium-sized EVs (mEVs) expressing 12-LOX. 12-LOX was detected in plasma mEV of patients with adenomas/ adenocarcinomas, implying their potential to deliver the protein to cancer cells in vivo. In cancer cells exposed to platelets, endogenous but not exogenous 12S-HETE contributed to changes in EMT gene expression, mitigated by three structurally unrelated 12-LOX inhibitors. In conclusion, we showed that platelets induce the generation of primarily esteri-fied 12-HETE in colon cancer cells following mEV-mediated delivery of 12-LOX. The modification of cancer cell phospholipids by 12-HETE may functionally impact cancer cell biology and represent a novel target for anticancer agent development.

Idioma: Inglés

DOI: 10.1016/j.jlr.2021.100109

Año: 2021

Publicado en: Journal of Lipid Research 62 (2021), 100109 [18 pp]
ISSN: 0022-2275

Factor impacto JCR: 6.676 (2021)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 60 / 297 = 0.202 (2021) - Q1 - T1

Factor impacto CITESCORE: 11.0 - Biochemistry, Genetics and Molecular Biology (Q1)

Factor impacto SCIMAGO: 1.817 - Cell Biology (Q1) - Biochemistry (Q1)

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI14-01218

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)