Profiling Lipoxygenase Metabolism in Specific Steps of Colorectal Tumorigenesis

Abstract

Lipoxygenases (LOX) are key enzymes for the oxidative metabolism of polyunsaturated fatty acids into biologically active products. Clinical data on comparative levels of various LOX products in tumorigenesis are lacking. Therefore, we examined the profiles of several LOX products (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2) 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 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 colon [mean, 36.11 ng/mg protein; 95% confidence interval (95% 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 colon (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 the right normal colon (mean, 32.46 ng/mg protein; 95% CI, 27.95-36.98; P = 0.09). No significant differences with regard to 12-or 15-hydroxyeicosatetraenoic acid or leukotriene B 4 levels were detected between normal, polyp, and cancer mucosae. 15-LOX-1 inhibited interleukin-1β expression. This study establishes that reduced 13-HODE levels are a specific alteration in the LOX product profile associated with human colorectal tumorigenesis. Cancer Prev Res; 3(7); 829-38. ©2010 AACR.

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention

“…Notably, high expression of 5-LOX was also observed in individual cells within the stroma, consistent with inflammatory cell phenotype, though inflammatory markers were not stained for in the same sections. In contrast to the study by Shurequi et al, [91], we observed a modest increase in expression of 12-LOX in many colorectal cancers, though both villous and tubulovillous adenomas expressed levels of 12-LOX similar to normal colon. While our study is only descriptive, it would suggest that 5-LOX expression is an early event in the sequence to colon cancer, with increased expression in adenoma frequent, while 12-LOX expression would appear to be a later event, possibly mediating invasion and metastasis.…”

“…A recent study by Shureiqi et al, examined 5-LOX, 12-LOX, 15-LOX-1 and 15-LOX-2 in a prospective study of 125 patients [91]. No differences in 12-or 15-HETE or leukotriene B(4) levels were observed between normal, polyp and cancer mucosae; however, the expression of the 15-LOX-1 product, 13(S)-HODE, was lost across this progressive sequence.…”

The role of 15-LOX-1 in colitis and colitis-associated colorectal cancer

“…Decreased expression of 15-LOX-1 in human CRC is associated with IL-1b upregulation; 15-LOX-1 re-expression in CRC cells inhibits IL-1b [89], which is a major proinflammatory cytokine that contributes to the pathogenesis of human colitis [93]. These results show that 15-LOX-1 may attenuate colitis by downregulating the expression of IL-1b.…”

“…These results indicate that 15-LOX-1 can serve as a tumor suppressor gene. Re-expressed 15-LOX-1 in CRC inhibits the expression of IL-6b [89], which is a major pro-inflammatory cytokine that contributes to the pathogenesis of human colitis [90]. STAT3 is activated in tumors from the lung, breast, kidneys, cervix, ovaries, head and neck, and prostate, as well as in pancreatic carcinoma, melanoma, colon carcinoma, gastric carcinoma, hepatocellular carcinoma, multiple myeloma, and chronic lymphocytic leukemia [91].…”

Curcumin Chemoprevention: The Long Road to Clinical Translation

“…Findings from this and the current study could be interpreted as suggesting that PGE 2 promotes colonic tumorigenesis at stages later than ACF and adenomas. Of note, a recently published study has showed no significant change in leukotriene B 4 levels during colonic tumorigenesis (33), calling into question whether 5-HETE really is a biomarker for colorectal tumorigenesis. The current study is limited in assessing the role of these pathways in colonic tumorigenesis by its relatively small sample size and single pathological endpoint.…”