15‐hydroxy‐eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator‐activated receptor gamma‐dependent pathway

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR␥) inhibits cell growth via promoting apoptosis. Human colorectal cancer tissues had abundant PPAR␥ but the incidence of apoptosis was very low, suggesting a defect in the PPAR␥ pathway. Here, we found that 15-hydroxy-eicosatetraenoic acid (15S-HETE), an endogenous ligand for PPAR␥, was significantly decreased in the serum of patients with colorectal cancer. Treatment of colon cancer cells with 15S-HETE inhibited cell proliferation and induced apoptosis, which was preceded by an increase in TGF-␤-inducible early gene (TIEG) and a decrease in Bcl-2. The action of 15S-HETE could be blocked when PPAR␥ was suppressed. Overexpression of Bcl-2 prevented the apoptosis. The levels of TIEG and 15-lipoxygenase (15-LOX), the enzyme responsible for 15S-HETE production, was decreased in colorectal cancer. Therefore, colorectal cancer is associated with decreased 15S-HETE. Treatment of colon cancer cells with 15S-HETE inhibits cell proliferation and induces apoptosis in a PPAR␥-dependent pathway involving augmentation of TIEG and reduction of Bcl-2 expression.

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

“…Expression of 15-LOX-1 correlates with tumorigenesis of PC-3 prostate cancer cells in vivo (24,29), yet exogenous 15(S)-HETE blocks the proliferation of these same cells in vitro (30,31). 15(S)-HETE arrests the growth of HT 29 colon cancer cells in some investigations (32) but not in others (33) arrests growth of CaCo-2, HT29, or RKO colon cancer cells. Two aspects of experimental design may contribute to these paradoxes.…”

“…The chemically stable HETE and HODE metabolites of 15-LOX-1 inhibit purified TrxR enzyme, but our data suggest that the metastable HpETEs and HpODEs, or their rearrangement product 4-HNE, also contribute to the inhibition of TrxR in cells. HETEs or HODEs bind weakly and reversibly with cellular receptors, including PPAR␦ (36) or PPAR␥ (31,32,37,44). If HETEs or HODEs alone were the inhibitory molecules, then TrxR activity should have recovered promptly.…”

“…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.…”

“…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. 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).…”

Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment

“…19,20 Furthermore, a number of metabolites generated by LOX15 can function as endogenous activators and ligands for PPARg. 21,22 A balance between a procarcinogenic effect as a PGE 2 precursor and an anticarcinogenic effect as a PPARg ligand might be a key concept to define the role of LA. In the present study, we designed an in vitro carcinogenesis model using IEC6 intestinal cells and evaluated the effect of LA on growth, genotoxicity and transformation by AOM.…”