15‐lipoxygenase‐1 exerts its tumor suppressive role by inhibiting nuclear factor‐kappa B via activation of PPAR gamma

Abstract

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 (IκBα), decreased nuclear translocation of p65 and p50, decreased DNA binding in the nucleus and decreased transcriptional activity of Nuclear factor kappa B (NF-κB). As the 15-LOX-1 enzymatic product 13(S)-HODE is known to be a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, and NF-κB can be inhibited by PPARγ, we examined whether activation of PPARγ was necessary for the abrogation of NF-κB activity. Our data show that the inhibition of both early and late stages of NF-κB activation could rescued by the PPARγ antagonist GW9662 indicating that the inhibition was most likely mediated via PPARγ.

Differential cell growth/apoptosis behavior of 13-hydroxyoctadecadienoic acid enantiomers in a colorectal cancer cell line

“…13(S)-HODE has been described as an agonist for PPAR␥ in colorectal cell lines (10,42). The activation of PPAR␥, a transcription factor that is expressed in epithelial cells and has been shown to inhibit cell proliferation, induces differentiation and promotes cell cycle arrest and apoptosis in colon cancer cell lines (13,19,30,49). Accordingly, our results indicate that 13(S)-HODE binds to PPAR␥ and that its antiproliferative effect is reverted in the presence of a PPAR␥ inhibitor, which reinforces the data that the binding of 13(S)-HODE to PPAR␥ possesses anti-tumorpromoting properties.…”

“…In this sense, 15-LOX metabolites have been shown to play both pro-and antitumorigenic actions, whereas COX metabolites are described to be tumorigenic (42). Thus, while the expression of 15-LOX-1 inhibited intestinal epithelial cell proliferation (12,13), the expression of COXs is mitogenic (15).…”

“…COX has two isoforms (COX-1 and COX-2) and produces prostaglandins (PGs) and thromboxanes. LOXs constitute a family of dioxygenases that insert molecular oxygen into free and/or esterified polyunsaturated fatty acids with regional specificity and are designated 5-, 8-, 12-and 15-LOX, accordingly (12,13). Thus these enzymes metabolize AA to the biologically active metabolites hydroperoxyeicosatetraenoic acids, which on reduction form corresponding hydroeicosatetranoic acids (HETEs), while the metabolism of linoleic acid preferentially results in the formation of hydroxyoctadecadienoic acids (HODEs).…”

PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide

“…c-MET; the inhibition of β-catenin signaling; increasing the expression of 15-LOX-1 with increased synthesis of the bioactive metabolites 13-S-HODE and 15-S-HETE, leading to activation of PPARγ [37–41]. This is of particular note because 15-LOX-1 expression and 13-S-HODE levels are suppressed in lung cancer cells and in other systems, sildenafil has been shown through PKG to regulate PPARγ [42, 43]. It is also known that PPARγ can regulate AMPK and eNOS signaling, which in our system using pemetrexed and sildenafil could be a point of convergence for the observed anti-cancer effects of both drugs [44].…”

Mammalian lipoxygenases and their biological relevance

“…In similar cellular models of colorectal carcinoma (HCT116, HT29) ALOX15 exhibited anti-carcinogenic properties, which was related to inhibition of the anti-apoptotic effect of the inflammatory transcription factor nuclear factor kappa B [127]. Here again, the molecular basis for the observed anti-carcinogenic affect is not completely understood but overexpression of ALOX15 inhibited the degradation of the inhibitor of kappa B, impaired nuclear translocation of p65 and p50, decreased DNA binding in the nucleus and reduced the transcriptional activity of NF-κB [128]. Unresolved chronic inflammation is a key process in tumor progression and thus, pro-resolving lipid mediators (eicosanoids and related metabolites of other polyenoic fatty acids) such as lipoxins [129], resolvins [130] and maresins [131] need to be discussed as regulators of carcinogenesis [132].…”