Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology

Abstract

The International Agency for Research on Cancer recently released an assessment classifying red and processed meat as "carcinogenic to humans" on the basis of the positive association between increased consumption and risk for colorectal cancer. Diet, however, can also decrease the risk for colorectal cancer and be used as a chemopreventive strategy. Bioactive dietary molecules, such as n-3 polyunsaturated fatty acids, curcumin, and fermentable fiber, have been proposed to exert chemoprotective effects, and their molecular mechanisms have been the focus of research in the dietary/chemoprevention field. Using these bioactives as examples, this review surveys the proposed mechanisms by which they exert their effects, from the nucleus to the cellular membrane. In addition, we discuss emerging technologies involving the culturing of colonic organoids to study the physiological effects of dietary bioactives. Finally, we address future challenges to the field regarding the identification of additional molecular mechanisms and other bioactive dietary molecules that can be utilized in our fight to reduce the incidence of colorectal cancer.

Keywords: colonic organoids; membrane organization; microRNAs; n-3 polyunsaturated fatty acids.

Figure 1

Effects of diet on promoting and preventing colorectal cancer. Compounds found in the diet have been linked to the development of colorectal cancer through the induction of DNA adducts, leading to mutations in oncogenic genes and promoting hyperproliferation and hyperplasia. Compounds found in many fruits, vegetables, and fish can counteract cancer-promoting compounds in a pleiotropic manner and therefore should be incorporated in a healthy human diet. Abbreviation: EGCG, epigallocatechin gallate.

Figure 2

Potential mechanisms by which bioactive dietary molecules mediate chemoprotective effects in the nucleus. Bioactive dietary molecules such as EPA, DHA, and curcumin can activate transcription factors that regulate chemoprotective genes or inhibit transcription factors that drive oncogenesis. These molecules can also affect miRNA silencing as well as alter posttranslational modification of histones. Abbreviations: ac, histone acetylation; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; me, histone methylation; miRNA, microRNA; p, histone phosphorylation; ub, histone ubiquitination.

Figure 3

Proposed mechanisms by which the interaction of dietary long-chain n-3 polyunsaturated fatty acids from fish oil and butyrate from bacterial fermentation of dietary fiber may reduce colon tumorigenesis. Butyrate induces colonocyte apoptosis via a nonmitochondrial, Fas-mediated, extrinsic pathway. Docosahexaenoic acid (DHA) and butyrate, in combination, synergistically perturb intracellular Ca²⁺, stimulating mitochondrial Ca²⁺ uptake. This directly or indirectly decreases cytosolic Ca²⁺ and promotes store-operated channel (SOC)-mediated entry via plasma membrane channels. Mitochondrial Ca²⁺ accumulation subsequently triggers the opening of the permeability transition pore (PTP) and release of proapoptotic molecules, such as cytochrome c, and other factors, such as apoptosis-inducing factor (AIF) and second mitochondrial activator of caspases (smac/Diablo). Together, these effects culminate in the induction of procaspases and downstream caspases (Casp) that execute cellular apoptosis. Abbreviations: Apaf1, apoptotic protease-activating factor 1; Cyt-c, cytochrome c; EndoG, endonuclease G; SERCA, sarcoendoplasmic reticulum Ca²⁺ ATPase.

Figure 4

Multiple pathways for the delivery of dietary bioactives to colonocytes. (a) Blood pathway. Polyunsaturated fatty acids are delivered to colonocytes and other cell types, such as T cells, through the bloodstream after digestion and absorption from the small intestine into the portal vein. In the colonocyte, the fatty acids are incorporated into phospholipids in the plasma membrane. Abbreviation: DHA, docosahexaenoic acid. (b) Intestinal pathway. Curcumin is poorly bioavailable and hence is transported, intact, to the colon, where it can intercalate between phospholipids in the plasma membrane of colonocytes. (c) Microbial pathway. Pectin is not digestible by human enzymes and therefore transits to the colon, where gut microbes ferment it to produce butyrate, which is rapidly taken up by colonocytes.

Figure 5

Culturing of colonic organoids. Colonic crypts, isolated from the colon by ethylenediamine tetra-acetic acid (EDTA) treatment, are cultured in Matrigel 3D matrix in media containing a mixture of recombinant growth factors. All cell lineages in the crypt are recapitulated in the developing organoid.