Biology and pharmacology of platelet-type 12-lipoxygenase in platelets, cancer cells, and their crosstalk

Annalisa Contursi; Stefania Tacconelli; Ulrika Hofling; Annalisa Bruno; Melania Dovizio; Patrizia Ballerini; Paola Patrignani

doi:10.1016/j.bcp.2022.115252

Biology and pharmacology of platelet-type 12-lipoxygenase in platelets, cancer cells, and their crosstalk

Biochem Pharmacol. 2022 Nov:205:115252. doi: 10.1016/j.bcp.2022.115252. Epub 2022 Sep 18.

Authors

Annalisa Contursi¹, Stefania Tacconelli¹, Ulrika Hofling¹, Annalisa Bruno¹, Melania Dovizio¹, Patrizia Ballerini², Paola Patrignani³

Affiliations

¹ Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy.
² Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, "G. d'Annunzio" University, Chieti, Italy.
³ Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy. Electronic address: ppatrignani@unich.it.

PMID: 36130648
DOI: 10.1016/j.bcp.2022.115252

Abstract

Platelet-type lipoxygenase (pl12-LOX), encoded by ALOX12, catalyzes the production of the lipid mediator 12S-hydroperoxyeicosa-5,8,10,14-tetraenoic acid (12S-HpETE), which is quickly reduced by cellular peroxidases to form 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12S-HETE). Platelets express high levels of pl12-LOX and generate considerable amounts of 12S-HETE from arachidonic acid (AA; C20:4, n-6). The development of sensitive chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods has allowed the accurate quantification of 12S-HETE in biological samples. Moreover, advances in the knowledge of the mechanism of action of 12S-HETE have been achieved. The orphan G-protein-coupled receptor 31 (GPR31) has been identified as the high-affinity 12S-HETE receptor. Moreover, upon platelet activation, 12S-HETE is produced, and significant amounts are found esterified to membrane phospholipids (PLs), such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), promoting thrombin generation. Platelets play many roles in cancer metastasis. Among them, the platelets' ability to interact with cancer cells and transfer platelet molecules by the release of extracellular vesicles (EVs) is noteworthy. Recently, it was found that platelets induce epithelial-mesenchymal transition(EMT) in cancer cells, a phenomenon known to confer high-grade malignancy, through the transfer of pl12-LOX contained in platelet-derived EVs. These cancer cells now generate 12-HETE, considered a key modulator of cancer metastasis. Interestingly, 12-HETE was mainly found esterified in plasmalogen phospholipids of cancer cells. This review summarizes the current knowledge on the regulation and functions of pl12-LOX in platelets and cancer cells and their crosstalk.Novel approaches to preventing cancer and metastasis by the pharmacological inhibition of pl12-LOX and the internalization of mEVs are discussed.

Keywords: 12-LOX inhibitors; Cancer; Extracellular vesicles; Metastasis; Platelet type 12-LOX; Platelets.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Arachidonate 12-Lipoxygenase*
Arachidonic Acid
Biology
Blood Platelets
Chromatography, Liquid
Hydroxyeicosatetraenoic Acids
Neoplasms*
Peroxidases
Phosphatidylcholines
Phosphatidylethanolamines
Plasmalogens
Tandem Mass Spectrometry
Thrombin

Substances

Arachidonate 12-Lipoxygenase
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Phosphatidylethanolamines
Arachidonic Acid
Thrombin
Plasmalogens
Phosphatidylcholines
Peroxidases
Hydroxyeicosatetraenoic Acids