Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers

Abstract

13-S-Hydroxyoctadecadienoic acid (13-S-HODE), the product of 15-lipoxygenase (15-LOX) metabolism of linoleic acid, enhances cellular mitogenic responses to certain growth factors. Other observations have questioned whether 13-S-HODE has tumorigenic effects. Our study evaluated the hypothesis that 15-LOX-1 is overexpressed in colon cancers resulting in an increase in intracellular 13-S-HODE. 15-LOX-1 and 13-S-HODE were quantified using western blots, ELISA and immunohistochemistry in 18 human colon cancers with paired normal colonic mucosa. Additionally, 15-LOX-1 expression was measured by western blots in three transformed colonic cell lines and in a human umbilical vein endothelial cell line. Next, we evaluated 13-S-HODE effects on cellular proliferation, cell cycle distribution and apoptosis in a transformed colonic cell line (RKO). Cell cycle distributions were measured by flow cytometry and apoptosis was assessed by phase contrast microscopy, electron microscopy, flow cytometry and DNA fragmentation assay. 15-LOX-1 immunohistochemistry staining scores were reduced in tumor tissues (P </= 0.0001) and 15-LOX-1 expression was absent in three transformed colonic cell lines. 13-S-HODE levels were also reduced in tumors tissues compared with normal controls by ELISA (median 3.3-fold, P = 0.02) and by immunohistochemistry (P </= 0.0001). In vitro 13-S-HODE inhibited RKO cell proliferation and induced cell cycle arrest and apoptosis. 13-S-HODE produced similar effects in HT-29 cells. Our observations indicate that: (i) human colon cancers are associated with a down-regulation in 15-LOX-1 expression and a reduction in 13-S-HODE intracellular levels; (ii) 13-S-HODE can suppress cell proliferation and induce apoptosis in transformed colonic epithelial cells.

Conditional Expression of 15-Lipoxygenase-1 Inhibits the Selenoenzyme Thioredoxin Reductase

“…Chen et al (32) found that the concentration of 15(S)-HETE in serum was ϳ60% lower in patients with colon cancer compared with normal patients. Our results are consistent with those reported by Shureiqi et al (35) and Chen et al (32), and with the hypothesis that loss of 15-LOX-1 expression favors malignant progression in colon tissue (17,34,39,35,32). For instance, loss of 15-LOX-1 would nullify its regulation of TrxR, the G 1 cell cycle checkpoint, and BAX expression.…”

“…Ikawa et al (50) found elevated expression of 15-LOX-1 in ϳ 60% (13/21) of colon tumors. In contrast, Shureiqi et al (35) found lower levels of 13(S)-HODE in 15/18 (ϳ 83%) colon tumors compared with normal tissue. Chen et al (32) found that the concentration of 15(S)-HETE in serum was ϳ60% lower in patients with colon cancer compared with normal patients.…”

“…In human cancers, expression of 15-LOX-1 correlates positively with the aggressiveness of prostate tumors (25), but not with colorectal tumors (35,32,50). The relationship between 15-LOX-1 and colorectal cancer is elusive.…”

Interleukin (IL)-4 Indirectly Suppresses IL-2 Production by Human T Lymphocytes via Peroxisome Proliferator-activated Receptor γ Activated by Macrophage-derived 12/15-Lipoxygenase Ligands

“…Determination of 13-HODE Levels by ELISA (19,20)-13-HODE was extracted from each sample at 4°C as follows. The solution was acidified to a pH of 3.5-4.0.…”

The 15-lipoxygenase-1 product 13- S -hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells

“…Restoring apoptosis is an important anticarcinogenic mechanism (2,4,5). Loss of apoptosis in colorectal cancer cells is linked to down-regulation in 15-lipoxygenase-1 (15-LOX-1) expression, and the primary product of 15-LOX-1 acting on linoleic acid, 13-S-hydroxyoctadecadienoic acid (13-S-HODE) (6), restores apoptosis in colorectal cancer cells (7). Nonsteroidal antiinf lammator y drugs (NSAIDs) induce apoptosis in colorectal cancer cells (8)(9)(10).…”