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ALOX15

12-LOX|15-LOX-1|15LOX-1;arachidonate 15-lipoxygenase;ALOX15;arachidonate 15-lipoxygenase

12/15-lipoxygenase|15-LOX|15-lipooxygenase-1|arachidonate 12-lipoxygenase, leukocyte-type|arachidonate omega-6 lipoxygenase

17p13.3

protein-coding

15-Lipoxygenase-1 (15-LOX-1) is an enzyme of the inflammatory eicosanoid pathway whose expression is known to be lost in colorectal cancer (CRC). We have previously shown that reintroduction of the gene in CRC cell lines slows proliferation and induces apoptosis (Cimen et al. [2009] cancer Sci 100: 2283-2291). We have hypothesized that 15-LOX-1 may be anti-tumorigenic by the inhibition of the anti-apoptotic inflammatory transcription factor nuclear factor kappa B. We show here that ectopic expression of 15-LOX-1 gene in HCT-116 and HT-29 CRC cell lines inhibited the degradation of inhibitor of kappa B (IkappaBalpha), decreased nuclear translocation of p65 and p50, decreased DNA binding in the nucleus and decreased transcriptional activity of Nuclear factor kappa B (NF-kappaB). As the 15-LOX-1 enzymatic product 13(S)-HODE is known to be a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, and NF-kappaB can be inhibited by PPARgamma, we examined whether activation of PPARgamma was necessary for the abrogation of NF-kappaB activity. Our data show that the inhibition of both early and late stages of NF-kappaB activation could rescued by the PPARgamma antagonist GW9662 indicating that the inhibition was most likely mediated via PPARgamma.

expression of 15-lipoxygenase-1 (15-LOX-1) is decreased in many human cancers; however, the mechanistic significance of its decreased expression has been difficult to determine because its mouse homolog 12/15-LOX has opposing functions. We generated a mouse model in which expression of a human 15-LOX-1 transgene was targeted to the intestinal epithelium via the villin promoter. Targeted expression was confirmed by real-time reverse transcription-polymerase chain reaction and immunoblotting. When the 15-LOX-1 transgene was expressed in colonic epithelial cells of two independent mouse lines (B6 and FVB), azoxymethane-inducible colonic tumorigenesis was suppressed (mean number of tumors: wild type [WT] = 8.2, 15-LOX-1(+/-) = 4.91, 15-LOX-1(+/+) = 3.57; WT vs 15-LOX-1(+/-) two-sided P = .003, WT vs 15-LOX-1(+/+) two-sided P < .001; n = 10-14 mice per group). 15-LOX-1 transgene expression was always decreased in the tumors that did develop. In the presence of expression of the 15-LOX-1 transgene, expression of tumor necrosis factor alpha and its target inducible nitric oxide synthase were decreased and activation of nuclear factor-kappa B in colonic epithelial cells was inhibited.