Mode Of Action Of Types Of Dietary Fats Against Colon Cancer

Successful approach for implementation of preventive strategies depends on a mechanistic understanding of carcinogenesis at the tissue, cellular, and molecular levels. Carcinogenesis is typically a slow, chronic process and the development of invasive disease is characterized by molecular derangements. Although the molecular mechanisms by which n-3 PUFAs inhibit colon carcinogenesis have not been fully elucidated, several putative mechanisms of action have been proposed for colon cancer preventive activity of types of dietary fat (Figure 23.2). As discussed in detail by Hong et al.,44 dietary n-3 PUFAs may protect against colon carcinogenesis by either decreasing DNA adduct formation and/or by enhancing DNA repair. Lower levels of AOM-induced DNA adducts were detected in fish oil-fed rats as compared to those fed corn oil, rich in n-6 PUFAs. Also, fish oil supplementation caused an increase in apoptosis in the colon compared with corn oil-fed rats.4445 It is therefore reasonable to conclude that one of the mechanisms by which n-3 PUFAs protect against colon carcinogenesis is in part by reducing the level of DNA-adducts and by enhancing the deletion of colonic cells through apoptosis.44

Metabolic epidemiological studies demonstrated that populations who are on a typical Western diet and at high risk for colon cancer excrete high levels of secondary bile acids.4647 Several preclinical studies indicate that diets high in saturated fatty acids (beef tallow and lard) and n-6 PUFAs (corn oil or safflower oil) increase the concentration of colonic luminal secondary bile acids including deoxycholic acid and lithocholic acid, whereas dietary fish oil had no such enhancing effect.31 Secondary bile acids have been shown to stimulate protein kinase C (PKC) in a manner similar to phorbol esters, to induce cell proliferation, to increase ornithine decarboxylase activity, a rate-limiting enzyme in polyamine biosynthesis, and to act as promoters in colon carcinogenesis.48-53 Collectively, these observations suggest that secondary bile acids that are modulated by types of dietary fat may be important for inducing cellular response in relation to colon tumor promotion.

There are studies to indicate that inducible nitric oxide (NO) synthase (iNOS), which is regulated primarily at the transcriptional levels is overexpressed in human colon adenomas54 and in colon tumors of laboratory animal models.55 Overproduction of NO by iNOS is critical to carcinogenesis process and induces deaminated DNA lesions, thus resulting in DNA damage.56 Both NO and perox-initrate produced in the tissues by NOS also activate cyclooxygenase (COX)-2. These data clearly suggest a key role for NO in tumor initiation, promotion, and progression. Studies conducted in our laboratory indicate that deoxycholic acid

FIGURE 23.2 Mechanisms by which n-3 PUFAs inhibit colon carcinogenesis. The schematic diagram illustrates potential cellular and molecular events mediated by n-3 PUFAs against colon carcinogenesis. The cascade of molecular events modulated by n-3 PUFAs includes proinflammatory genes such as COX-2 and iNOS, activated ras, specific PKC isoforms, and differentiating factors including RXR that modulate cell differentiation and apoptosis. High dietary n-3 PUFAs exert antitumor activity by interfering with the post-translational modification and membrane localization of ras-p21 through modulation of farnesyl protein transferase, thus inhibiting ras-p21 function.

FIGURE 23.2 Mechanisms by which n-3 PUFAs inhibit colon carcinogenesis. The schematic diagram illustrates potential cellular and molecular events mediated by n-3 PUFAs against colon carcinogenesis. The cascade of molecular events modulated by n-3 PUFAs includes proinflammatory genes such as COX-2 and iNOS, activated ras, specific PKC isoforms, and differentiating factors including RXR that modulate cell differentiation and apoptosis. High dietary n-3 PUFAs exert antitumor activity by interfering with the post-translational modification and membrane localization of ras-p21 through modulation of farnesyl protein transferase, thus inhibiting ras-p21 function.

induces iNOS activity in intestinal cells suggesting that one of the mechanisms by which tumor promoters including secondary bile acids may involve an increase in expression of iNOS through an activation pathway that enhances colon car-cinogenesis.57

It is known that the fatty acid composition of cells is sensitive to diet. Studies conducted in our laboratory indicate that increasing levels of dietary fish oil in rats increased the omega-3 fatty acids, namely, DHA and EPA, in the colonic mucosal membrane phospholipid fractions at the expense of omega-6 PUFAs such as linoleic acid and arachidonic acid. This suggests that the DHA and EPA of fish oil can modulate the activity of membrane-bound enzymes by partially replacing arachidonic acid and linoleic acid in the phospholipid pool.58 It is well established that arachidonic acid and some of its metabolites including prostag-landins (PGs) play an important role in the intracellular signaling pathway associated with cell proliferation and gene expression. PGs increase cell proliferation, promote angiogenesis, and inhibit immune surveillance, all of which are involved in tumor growth.

It has been shown that inhibition of colon carcinogenesis by DHA is mediated through the activation of retinoid X receptors (RXR), an obligatory component of a large number of nuclear receptors.59 This observation suggests that n-3 PUFAs mediate growth inhibitory effects in the colon through the RXR subunit of nuclear receptor heterodimers. Members of the nuclear-receptor superfamily are transcription factors that selectively regulate cell differentiation and proliferation, many of which are important sites for carcinogenesis making their ligands an ideal target for prevention.60

Overexpression of COX-2 plays an important role in colon carcinogenesis.61 Tsujii and DuBois62 have shown that overexpression of COX-2 can lead to the suppression of apoptosis. High intake of saturated fat and n-6 PUFAs alters membrane phospholipid turnover, releasing membrane arachidonic acid from phospholipids, and affecting prostaglandin synthesis via COX enzyme.2835 Elevated levels of COX-2 have been observed in human colon tumors and chemically induced colon tumors in rodents.6364 Recent reports have shown a link between the tumorigenic potential of APC mutations and arachidonic metabolism by the observation that deletion of the COX-2 gene reduces the number of tumors in mice heterozygous for an APC716 by more than sixfold.65 Of some interest, additional evidence supporting a role for COX-2 comes from our studies, which showed a marked reduction in colon tumors in rodents treated with a highly selective COX-2 inhibitor, celecoxib.24 Our recent laboratory results have provided convincing evidence that a high-fat mixed lipid (HFML) diet enhances AOM-induced expression of COX-2 and eicosanoid formation from arachidonic acid in colon tumors of rats whereas the high-fat fish oil (HFFO) diet inhibits the levels of COX-2. These results suggest that inhibition of eicosanoid production through the modulation of COX-2 activity may be important for ability of n-3 PUFAs to inhibit colon tumorigenesis.12 Also, colon tumors of animals fed the HFML diet showed a nearly 50% lower apoptotic index than was observed in the colon tumors of rats fed the HFFO diet. These results suggest that the overexpression of COX-2 in the tumors of animals fed the HFML diet in contrast to HFFO diet inhibits apoptosis and the consequent tumor burden. These results also support the contention that overexpression of COX-2 can lead to the suppression of apoptosis. A major question that remains to be answered is which signaling pathways are involved downstream of the COX-2 enzyme. These could provide not only a key link between dietary fatty acids, eicosanoids, COX-2, and transcriptional regulation of colon carcinogenesis, but also provide additional molecular targets for colon cancer prevention strategies.

Recent studies from our laboratory have shown that high dietary n-6 PUFAs enhance activities of diverse enzymes including protein kinases (PKC) whereas high-fat diet containing n-3 PUFAs appears to suppress the activities of these enzymes.65 Members of PKCs include several isoenzymes with unique functions. Specific PKC isoenzymes translocate to the membrane from the cytosol upon activation.66 67 Jiang et al.68 reported that chemopreventive efficacy of dietary fish oil is associated with the alterations in colonic PKC expression that is activated upon stimulation by growth factors. PUFAs may influence the activity of the EGF receptor/mitogen-activated protein kinase pathway, which could alter the expression of a number of oncogenes. It is interesting that several kinases have been shown to participate in ras-mediated growth-promoting signal transduction pathways.69 The ras-p21, a guanine nucleotide-binding 21-kDa protein product of ras genes, is anchored to the cytoplasmic face of plasma membrane and functions in the regulation of cell proliferation. Mutational versions of ras-p21 are implicated in the etiology of human colon cancer.70 It is also known that trafficking of proras from cytosol to plasma membrane is facilitated by a series of closely linked post-translational modifications including farnesylation, which is catalyzed by farnesyl protein transferase (FPTase). It appears that inhibition of ras farnesylation blocks membrane association of ras-p21 and prevents neoplastic transformation of cells. Studies conducted in our laboratory have provided data to indicate that high dietary n-6 PUFAs increase ras-p21 expression in colonic tumors, whereas high dietary n-3 PUFAs interfere with post-translational modification and membrane localization of ras-p21 through the modulation of FPTase activity, thus inhibiting ras-p21 function.71

Additional studies conducted in our laboratory have demonstrated that DHA inhibits growth of CaCo-2 colon cancer cells in vitro and induces apoptosis.72 The effects of DHA on the genetic precursors of human colon cancer were also analyzed in CaCo-2 cells using DNA oligonucleotide arrays.73 DHA treatment modulated multiple signaling pathways involved in the regulation of cell cycle regulatory genes, COX-2 target genes, lipoxygenases, and peroxisome prolifera-tors. Effects of DHA on cell cycle progression and induction of apoptosis were directly paralleled by an increase in the activation of several proapoptotic caspases, inactivation of antiapoptotic Bcl-2 family of genes and activation of cyclin-dependent kinase inhibitors such as p21waf1/cip1 and p27. Comprehensive evaluation of the role of the apoptosis-related genes in colon cancer continues as the protein products of these genes suggest themselves as molecular targets for effective intervention by selective chemopreventive agents including nutritional factors.

Keep Your Weight In Check During The Holidays

Keep Your Weight In Check During The Holidays

A time for giving and receiving, getting closer with the ones we love and marking the end of another year and all the eating also. We eat because the food is yummy and plentiful but we don't usually count calories at this time of year. This book will help you do just this.

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