Saturated Fatty Acids Up-regulate COX-2 Expression in Prostate Epithelial Cells via Toll-like Receptor 4/NF-κB Signaling

Abstract

Cyclooxygenase-2 (COX-2) has been implicated in prostate carcinogenesis, and recently it has been confirmed to be a molecular target of saturated fatty acids (SFAs). In the present study, we investigated the effect of stearic acid (SA) and palmitic acid (PA), two of the most abundant SFAs contained in dietary fat, on COX-2 expression in prostate epithelial cells and the signaling transduction pathway involved. First, we demonstrated that both SA and PA increased the mRNA and protein expression of COX-2, and consistently induced the activation of NF-κB in RWPE-1, BPH-1 and PC-3 prostate epithelial cell lines. The effect of SA and PA on COX-2 over-expression and NF-κB activation was in a dose-dependent manner, and PA was more potent than SA at the same concentration. Then, we demonstrated inhibition of NF-κB using its specific inhibitor strikingly attenuated PA-induced COX-2 expression. Toll-like receptor 4 (TLR4) was revealed to be expressed on RWPE-1, BPH-1 and PC-3 cell lines by PCR and immunofluorescence staining, and blocking its signaling significantly inhibited PA induced COX-2 over-expression and NF-κB activation. Taken together, we demonstrated that SFAs can up-regulate COX-2 expression in prostate epithelial cells, and this effect was mediated mainly through the TLR4/NF-κB signaling pathway.

<p>Saturated Fatty Acids in Obesity-Associated Inflammation</p>

“…35 Both stearic acid and palmitic acid induce the activation of NF-κB and stimulate the secretion of pro-inflammatory mediators in trophoblast cells isolated from human placentas, 36,37 microglial cells, 38 and prostate epithelial cells. 39 Similarly, palmitic acid significantly activates JNK in HEPG2 cells; 40 increases the expression of MCP-1 in mesangial cells; 15 induces the expression of IL-6, IL-8, and MCP-1 in smooth muscle cells; 41,42 increases the activation of p38, JNK, and NF-κB with enhanced expression of TNFα in C2C12 skeletal muscle cells; 43,44 enhances the activation of NF-κB with increased production of IL-6 and TNF-α in adipocytes; 23,45 and induces the activation of p38, ERK, and JNK with increased expression of COX-2, IL-6 and MCP-1 in fibroblast cells. 46,47 Dietary supplementation with high-fat diet (HFD) or infusion of Liposyn II (a 20% triglyceride nonpyrogenic emulsion), lipid/heparin, soybean oil, lard oil, or fatty acids has been used to increase circulating FFA level in human and animal model studies.…”

Correlation between Oxidative Stress, Nutrition, and Cancer Initiation

“…In the broad literature regarding this type of EFA (omega-3, omega-6, and omega-3/omega-6 ratio) and its relationship to cancer progression, several underlying mechanisms have been hypothesized. One of the most established mechanisms is an association between inflammatory pathways and the function of omega-3 and omega-6 FAs on the action of cyclooxygenase-2 (COX-2) in prostate cancer [ 134 , 135 , 136 ]. On the contrary, Gao et al [ 193 ] demonstrated that palmitate, a saturated FA, up-regulated COX-2 via NF-κB-dependent mechanism; consequently, COX-2-associated oxidative stress weakened endothelium-dependent relaxations in the mouse aortas.…”

Fast food fever: reviewing the impacts of the Western diet on immunity

“…While saturated fats are the most inflammatory [50,61,62], overabundance of omega-6 (n-6) poly-unsaturated fats, such as those found in most cooking oils, have also been implicated in immune response through several mechanisms including effects on TLR4 [53] and serving as precursors for inflammatory mediators [63-67]. However, a recent review of human trials seems to undermine evidence supporting n-6 intake increases inflammation [68].…”