Abstract 2897: Profiling lipoxygenase metabolism in specific steps of colorectal tumorigenesis

Abstract

Abstract Lipoxygenases (LOXs) are key enzymes for the oxidative metabolism of polyunsaturated fatty acids into products that influence cell signaling, structure, and metabolism. Previous data on comparative levels of various LOX products in human tumorigenesis are limited primarily to retrospectively collected surgical samples from cancer patients. Therefore, we examined LOX product profiles by liquid chromatography/tandem mass spectrometry in the major steps of colorectal tumorigenesis (normal, polyp, and cancer) in a clinical study of 125 subjects (49 with a normal colon, 36 with colorectal polyps, and 40 with colorectal cancer) who underwent prospective colorectal biopsies to control for various potential confounding factors (e.g. diet, medications). Mean 13-hydroxyoctadecadienoic acid (13-HODE) levels were significantly higher in normal colons (mean = 36.11 ng/mg protein, 95% confidence interval [CI]: 31.56-40.67) than in paired colorectal cancer mucosa (mean = 27.01 ng/mg protein, 95% CI: 22.00-32.02; P = 0.0002) and in normal colons (mean = 37.15 ng/mg protein, 95% CI: 31.95-42.34) than in paired colorectal polyp mucosa (mean = 28.07 ng/mg protein, 95% CI: 23.66-32.48; P < 0.001). Mean 13-HODE levels, however, were similar between the left (mean = 37.15 ng/mg protein, 95% CI: 31.95-42.35) and right normal colons (mean = 32.46 ng/mg protein, 95% CI: 27.95-36.98; P = 0.09). No significant differences with regard to 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, or leukotriene B4 (LTB4) levels were detected between normal, polyp and cancer mucosa. Downregulation of 15-LOX-1 expression, the rate limiting enzyme for 13-HODE production, in human colorectal neoplastic mucosa was confirmed by quantitative real time PCR in a subset colorectal cancer patients for whom samples with adequate RNA quality were available. This study establishes that reduced 13-HODE levels are a specific alteration in the LOX product profile associated with human colorectal tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2897.