Abstract
Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. The arachidonic acid (AA) pathway and linoleic acid (LA) pathway have been implicated as important contributors to CRC development and growth. Human 15-lipoxygenase 1 (15-LOX-1) converts LA to anti-tumor 13-S-hydroxyoctadecadienoic acid (13-HODE)and 15-LOX-2 converts AA to 15-hydroxyeicosatetraenoic acid (15-HETE). In addition, human 12-LOX metabolizes AA to pro-tumor 12-HETE. In rodents, the function of 12-LOX and 15-LOX-1 and 15-LOX-2 is carried out by a single enzyme, 12/15-LOX. As a result, conflicting conclusions concerning the role of 12-LOX and 15-LOX have been obtained in animal studies. In the present studies, we determined that PD146176, a selective 15-LOX-1 inhibitor, markedly suppressed 13-HODE generation in human colon cancer HCA-7 cells and HCA-7 tumors, in association with increased tumor growth. In contrast, PD146176 treatment led to decreases in 12-HETE generation in mouse colon cancer MC38 cells and MC38 tumors, in association with tumor inhibition. Surprisingly, deletion of host 12/15-LOX alone led to increased MC38 tumor growth, in association with decreased tumor 13-HODE levels, possibly due to inhibition of 12/15-LOX activity in stroma. Therefore, the effect of 12/15-LOX on colorectal tumorigenesis in mouse models could be affected by tumor cell type (human or mouse), relative 12/15 LOX activity in tumor cells and stroma as well as the relative tumor 13-HODE and 12-HETE levels.
Highlights
Arachidonic acid (AA), a polyunsaturated omega-6 fatty acid, is a component of the phospholipid domain of most cell membranes[1]
Arachidonic acid metabolites derived from the cyclooxygenase, the LOX or the cytochrome P450 pathway have all been implicated in colorectal tumorigenesis[2,3,4]
To investigate the potential role of 15-LOX in mouse and human colorectal tumorigenesis, mouse colon adenocarcinoma MC38 cells and human colon adenocarcinoma HCA-7 cells were used for mouse and human colonic tumor growth experiments
Summary
Arachidonic acid (AA), a polyunsaturated omega-6 fatty acid, is a component of the phospholipid domain of most cell membranes[1]. AA is cleaved from membrane phospholipids by cytosolic phospholipase A2 and metabolized to eicosanoids by three main pathways: the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway, and the cytochrome P450 pathway. The cyclooxygenase pathway generates prostanoids, including prostaglandins (PGEs) and thromboxane; the lipoxygenase pathway produces leukotrienes and hydroxyeicosatetraenoic acids (HETEs). Arachidonic acid metabolites derived from the cyclooxygenase, the LOX or the cytochrome P450 pathway have all been implicated in colorectal tumorigenesis[2,3,4]. COX-derived PGE2 is the major prostanoids to promote colorectal tumorigenesis[5]. Both 5-LOX-derived leukotrienes and 5-HETE have been implicated in colorectal tumorigenesis[6,7,8,9,10]. Either genetic or pharmacologic inhibition of 5-LOX pathway suppresses colorectal tumorigenesis in murine models[3, 8,9,10,11]
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