Is 15-LOX-1 a Tumor Suppressor?

Abstract

A number of enzymes in the cyclooxygenase and lipoxygenase pathways process fatty acids to generate a variety of bioactive lipids. Recent findings that link inflammation to carcinogenesis have started to reveal how these bioactive lipids function in cellular signaling pathways as lipid messengers that mediate responses to cellular injury through inflammatory processes (1). Downstream effects of these bioactive lipids are determined by tissue-specific isomerases and specific receptors present in different organs. Two main pathways lead to the generation of bioactive lipids, which differ markedly in their biological activities. The cyclooxygenases lead mostly to the generation of prostaglandins and thromboxanes, whereas the lipoxygenases lead to the formation of leukotrienes and lipoxins among other products (Figure 1). Collectively, these signaling 20-carbon fatty acids are termed eicosanoids. They act by autocrine and paracrine mechanisms to regulate the dynamics of inflammation, immunity, and smooth muscle contraction and as messengers in the central nervous system (1,2). It is not surprising that many of these bioactive molecules play a critical role in inflammation, but their opposing functions are often underappreciated. The role of inflammation in carcinogenesis is well established and has been summarized by Wang and Dubois (1); however, important questions remain. It is still not clear which specific component(s) or which phase(s) of the inflammatory process are involved in carcino genesis or at which stage of carcinogenesis the primary effects of inflammation occur. Furthermore, the key question of whether inflam mation alone is sufficient and necessary to promote carcinogenesis in some settings is still unanswered. If so, a strategy that reverses inflam mation might be used to prevent and treat some types of cancer. Unsaturated fatty acids and metabolites of arachidonic and linoleic acids form bioactive lipids that function in the initiation, maintenance, and resolution of inflammation. Colorectal epithelium may be espe cially susceptible to the effects of bioactive lipids because of its direct proximity to their dietary sources. Lipoxygenases are lipid-peroxidizing enzymes that catalyze the dioxygenation of polyunsaturated fatty acids. More work is needed to fully understand the complex nature of these bioactive lipids in diverse biologic processes, but more and more evidence is emerging that suggests that lipoxygenases have many important roles in human diseases including cancer. Two different 15-lipoxygenase enzymes, 15-LOX-1 and 15-LOX-2, are found in humans, with distinct expression patterns throughout the body. The functions of the 15-LOX-1 enzyme and its products, 15-S-hydroxyeicosatetraenoic acid (15-S-HETE) and 13-S-hydroxyoctadecadienoic acid (13-S-HODE), are diverse; reportedly, they are chemoattractants for neutrophils (3), inhibit the production of superoxide by macrophages, affect the expression of adhesion molecules (4), and inhibit nuclear factor-kB (NF-kB), whereas they activate peroxisome proliferator–activated receptorg (PPAR-g) (5). Expression of 15-LOX-1 in cancer cell lines has