Mechanisms by Which Pleiotropic Amphiphilic n−3 PUFA Reduce Colon Cancer Risk

Abstract

Colorectal cancer is one of the major causes of cancer-related mortality in both men and women worldwide. Genetic susceptibility and diet are primary determinants of cancer risk and tumor behavior. Experimental, epidemiological, and clinical data substantiate the beneficial role of n–3 polyunsaturated fatty acids (PUFA) in preventing chronic inflammation and colon cancer. From a mechanistic perspective, n–3 PUFA are pleiotropic and multifaceted with respect to their molecular mechanisms of action. For example, this class of dietary lipid uniquely alters membrane structure/ cytoskeletal function, impacting membrane receptor function and downstream signaling cascades, including gene expression profiles and cell phenotype. In addition, n–3 PUFA can synergize with other potential anti-tumor agents, such as fermentable fiber and curcumin. With the rising prevalence of diet-induced obesity, there is also an urgent need to elucidate the link between chronic inflammation in adipose tissue and colon cancer risk in obesity. In this review, we will summarize recent developments linking n–3 PUFA intake, membrane alterations, epigenetic modulation, and effects on obesity-associated colon cancer risk.

Emerging role of chemoprotective agents in the dynamic shaping of plasma membrane organization

“…These microbial metabolites can interact with the apical membranes of colonic epithelial cells (Figure 1). Recent evidence from our lab and others suggest that the phenolic compound (+)-catechin, and its dimeric form procyanidin B2 can alter the biophysical properties of cell plasma membranes[82,83] (Figure 2), similar to what has been observed with other MTDB’s such as n-3 PUFA and curcumin[8,84–86]. Interestingly, walnuts have been shown to inhibit the growth of human cancer cell lines[87,88], and colon cancer in mouse models[89–91], similar to what has been demonstrated with other MTDB’s such as n-3 PUFA[8,23,69,92–95].…”

“…These microbial metabolites interact with the apical membranes of colonic epithelial cells (Figure 1). Recent evidence from our lab and others suggest that the phenolic compound (+)-catechin, and its dimeric form procyanidin B2 can alter the biophysical properties of cell plasma membranes[82,83] (Figure 2), similar to what has been observed with other MTDB’s such as n-3 PUFA and curcumin[8,84–86]. These findings are consistent with previous observations that procyanidins have the ability to modulate membrane biophysical properties[82,83].…”

“…For example, EPA and DHA, whose levels are readily influenced by diet in general [130], affect diverse physiological processes including cell membrane structure/function and signaling[8,84]. n–3 PUFA are rapidly incorporated into cells, primarily into membrane phospholipids at the sn -2 position[131,132].…”

Chemoprotective Epigenetic Mechanisms in a Colorectal Cancer Model: Modulation by n-3 PUFA in Combination With Fermentable Fiber

“…miRNAs modulated by fish oil in colon cancer in both human and rodent models have also been reported [11, 89] [90]*. Specific miRNAs influenced by fish oil treatment or the highly chemoprotective combination of fish oil and pectin diet are summarized with respect to their validated mRNA target genes in Table 1.…”

Fatty Acids and Membrane Lipidomics in Oncology: A Cross-Road of Nutritional, Signaling and Metabolic Pathways

“…The attenuation of oncogenic protein activity by modulating the membrane organization of essential proteins and lipids was proven and this is a promising way to use such an approach to manage cancer expansion. It is worth underlining that omega-3 has a very potent influence on membrane organization and this ability, combined with the anti-inflammatory activity, should be developed toward successful cancer treatments [ 171 , 172 ]. However, it is also evident that, without assessing the membrane status in the individual, the assignment of the lipid strategy cannot be precise, in types and doses, thus even bringing about contrasting clinical outcomes since the membrane unbalance results or remains altered.…”