Contursi, Annalisa, Schiavone, Simone, Dovizio, Melania, Hinz, Christine, Fullone, Rosa, Tacconelli, Stefania, Tyrrell, Victoria J., Grande, Rosalia, Lanuti, Paola, Marchisio, Marco, Zucchelli, Mirco, Ballerini, Patrizia, Lanas, Angel, O'Donnell, Valerie B. and Patrignani, Paola 2021. Platelets induce free and phospholipid-esterified 12-hydroxyeicosatetraenoic acid generation in colon cancer cells by delivering 12-lipoxygenase. Journal of Lipid Research 62 , 100109. 10.1016/j.jlr.2021.100109 |
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Abstract
Platelets promote tumor metastasis by inducing promalignant phenotypes in cancer cells and directly contributing to cancer-related thrombotic 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 platelets, 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 molecular 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 acquired 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 esterified 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.
Item Type: | Article |
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Date Type: | Published Online |
Status: | Published |
Schools: | Medicine |
Additional Information: | This is an open access article under the CC BY-NC-ND license |
Publisher: | American Society for Biochemistry and Molecular Biology |
ISSN: | 0022-2275 |
Date of First Compliant Deposit: | 7 October 2021 |
Date of Acceptance: | 7 August 2021 |
Last Modified: | 23 May 2023 16:02 |
URI: | https://orca.cardiff.ac.uk/id/eprint/144717 |
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