Eicosanoids and cancer

Abstract

Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.

Figure 1

General overview of series-2 prostanoid biosynthesis. After being released from membrane phospholipids (PLs) by the action of cytosolic phospholipase A₂ (cPLA₂), arachidonic acid is converted by cyclooxygenase 1 or 2 (COX1 or COX2) to an unstable intermediate, prostaglandin H₂ (PGH₂), which is rapidly converted to the PGs PGE₂, PGD₂, PGF_2α, PGI₂, and thromboxane A₂ by their specific synthases. Membrane PL cleavage also results in the release of lysophosphatidylcholine, which can be converted to platelet-activating factor (PAF). Prostanoids, thromboxanes and PAF are then released from the cell and can exert a wide range of actions mediated by binding to their specific G protein-coupled receptors, EP1–4, DP1–2, FP, IP, TP and PAFR.

Figure 2

General overview of leukotriene biosynthesis. After being released from membrane phospholipids (PLs) by the action of cytosolic phospholipase A₂ (cPLA₂), arachidonic acid is converted by the lipoxygenases (LOXs) 5-LOX, 12-LOX and 15-LOX-1 or 15-LOX-2 to the corresponding hydroperoxyeicosatetraenoic acid (HpETE) - 5-HpETE, 12-HpETE or 15-HpETE. These are rapidly converted to hydroxyeicosatetraenoic acids (HETEs) - 5-HETE, 12-HETE and 15-HETE. In addition, 5-HpETE is catalyzed by 5-LOX to form the unstable leukotriene LTA₄, which, through the action of LTA₄ hydrolase, results in the synthesis of LTB₄. Alternatively, LTA₄ can be converted into the cysteinyl leukotriene LTC₄ by the action of LTC₄ synthase. LTC₄ can then be converted to LTD₄ and LTE₄. Linoleic acid (LA) can be metabolized by 15-LOX producing 13-hydroperoxyoctadecadienoic acid (13-HpODE), which is then metabolized to 13-hydroxyoctadecadienoic acid (13-HODE). 15-HpETE can also be catalyzed by 5-LOX, often transcellularly, to produce lipoxin A₄ (LXA₄). Leukotrienes and HETEs are then released from the cell and can exert a wide range of actions mediated by binding to their specific receptors, BLT1-BLT2, CysLTR1-CysLTR2 and 12-HETER.