The lipid peroxidation product EKODE exacerbates colonic inflammation and colon tumorigenesis

Abstract

Oxidative stress is emerging as an important contributor to the pathogenesis of colorectal cancer (CRC), however, the molecular mechanisms by which the disturbed redox balance regulates CRC development remain undefined. Using a liquid chromatography–tandem mass spectrometry-based lipidomics, we found that epoxyketooctadecenoic acid (EKODE), which is a lipid peroxidation product, was among the most dramatically increased lipid molecules in the colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. This is, at least in part, due to increased oxidative stress in colon tumors, as assessed by analyzing gene expression of oxidative markers in AOM/DSS-induced CRC mice and human CRC patients in the Cancer Genome Atlas (TCGA) database. Systemic, short-time treatment with low-dose EKODE increased the severity of DSS-induced colitis, caused intestinal barrier dysfunction and enhanced lipopolysaccharide (LPS)/bacterial translocation, and exacerbates the development of AOM/DSS-induced CRC in mice. Furthermore, treatment with EKODE, at nM doses, induced inflammatory responses via JNK-dependent mechanisms in both colon cancer cells and macrophage cells. Overall, these results demonstrate that the lipid peroxidation product EKODE is an important mediator of colonic inflammation and colon tumorigenesis, providing a novel mechanistic linkage between oxidative stress and CRC development.

Roles of Lipid Peroxidation-Derived Electrophiles in Pathogenesis of Colonic Inflammation and Colon Cancer

“…In agreement with these studies, we showed that compared with control healthy mice, the AOM/DSS-induced CRC mice had a lower colonic expression of a series of anti-oxidative genes, such as Sod1 (encoding superoxide dismutase 1), Cat (encoding catalase), Gsr (encoding glutathione-disulfide reductase), Gsta1 (encoding glutathione S-transferase A1), Gstm1 (encoding glutathione S-transferase M1), and Hmox1 (encoding heme oxygenase-1), and had higher colonic expression of a pro-oxidative gene Mpo (encoding myeloperoxidase), demonstrating more severe redox stress in the colon tissues of AOM/DSS-induced CRC mice. Consistent with these findings in animal models, we found that, in the Cancer Genome Atlas (TCGA) database, the expressions of the anti-oxidant genes (CAT, GSR, GSTA1, GSTM1, and HMOX1) are reduced, while the expression of pro-oxidant gene MPO is increased, in the tumor samples of human CRC patients (Lei et al, 2021).…”

“…We found that EKODE was significantly increased in the colon of the AOM/DSS-induced C57BL/6 mice compared with that of the healthy control mice. In addition, EKODE was also among the most dramatically increased fatty acid metabolites in the colon of the mice (Lei et al, 2021). The concentration of EKODE was not significantly increased in the plasma of AOM/DSS-induced CRC mice compared with the healthy control mice (Wang et al, 2019b), and this could be due to the low chemical and/or metabolic stability of EKODE in circulation.…”

“…Previous studies also showed that the concentrations of LDEs are increased in animal models of CRC (Table 1). Our recent research showed that EKODE, an aldehyde compound derived from oxidative degradation of ω-6 PUFAs (Lin et al, 2007), was increased in the colon tissues of AOM/DSS-induced CRC mice (Lei et al, 2021). In our research, we used a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics, which can measure >100 fatty acid metabolites derived from both enzymatic metabolism and non-enzymatic oxidation of PUFAs (Wang et al, 2019b), to systematically profile how fatty acid metabolites are deregulated in the colon of AOM/DSS-induced CRC mice.…”

“…Previous studies by us and others showed that treatment with low-concentration LDE increases inflammatory responses. In our recent study, we treated human CRC (HCT-116) and mouse macrophage (RAW 264.7) cells with EKODE, at a concentration of 300 nM (a dose determined from LC-MS/MS analysis of the concentration of endogenous EKODE in the colon tissues of AOM/DSS-induced CRC mice, see our publication Lei et al, 2021). We found that EKODE treatment induces the expression of pro-inflammatory genes and activates JNK and NF-κB pathways in both CRC and macrophage cells, illustrating a potent pro-inflammatory effect of EKODE in vitro (Lei et al, 2021).…”

“…To address these concerns, recently we performed a series of animal studies to investigate the effects and mechanisms of LDEs, including 4-HNE, tt-DDE, and EKODE, on development of IBD and CRC in mouse models (Wang et al, 2019a(Wang et al, , 2020Lei et al, 2021). Our results showed that systematic, short-time, treatment with low doses of these compounds increased the severity of dextran sodium sulfate (DSS)-induced colitis and exacerbated the development of azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice, supporting a critical role of these compounds in the development of IBD and CRC in vivo (Wang et al, 2019a(Wang et al, , 2020Lei et al, 2021). In this review, we will discuss the roles of the LDEs in the pathogenesis of IBD and CRC, and the implications of LDEs in designing strategies to reduce the risks of IBD and CRC (Figure 1).…”