Figure 2. Proposed inflammatory mechanisms relating diet,…
Figure 2. Proposed inflammatory mechanisms relating diet, lifestyle, and medication use to colorectal cancer
Dietary…
Figure 2. Proposed inflammatory mechanisms relating diet, lifestyle, and medication use to colorectal cancerDietary components (e.g. vitamin D and n-3 fatty acids), lifestyle factors (e.g. physical activity), and medications (e.g. aspirin, COX-2 inhibitors, NSAIDs), might have anticancer effects (red lines) whereas lifestyle factors such as obesity could promote cancer (black lines) through anti-inflammatory mechanisms that are largely mediated through inhibition of the COX-2 enzyme. COX-2 could be upregulated by inflammatory or oncogenic stimuli via inflammatory cytokines such as or interleukin-6 (IL-6) or others that induce nuclear factor κB (NF-κB). COX-2 converts membrane-associated arachidonic acid to prostaglandins, including PGH2, PGD2, PGF2α, PGI2 (prostacyclin), and thromboxane A2, as well as PGE2. In turn, PGE2 stimulates EP2, which upregulates transcriptional activity of β-catenin and activates the oncogene products phosphatidylinositol-3-kinase (PI3K) and the kinase AKT. PGE2 also stimulates EP4, which triggers phosphorylation of the epidermal growth factor receptor (EGFR), thereby activating PI3K, AKT, and the oncogenic RAS–mitogen-activated protein kinase (MAPK) cascade. PGE2 stimulation of PI3K signaling also activates the transcriptional activity of the peroxisome-proliferator–activated receptor δ (PPAR δ). These PGE2-induced signaling pathways induce expression of a number of genes, including the angiogenic factor vascular endothelial growth factor (VEGF), the anti-apoptotic factor Bcl-2, and the proliferation-promoting factor cyclin D1. Many of the downstream targets of PGE2 act in positive feedback loops to induce greater expression of COX-2 (green arrows). Aspirin and NSAIDs might also directly stimulate PPARs, and block phosphorylation of AKT. 15-prostaglandin dehydrogenase (15-PGDH) inhibits PGE2 and thereby functions as a prostaglandin-degrading enzyme.– Upregulation of prostaglandin synthesis increases urinary 11 α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of PGE2.
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