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. 2008:1:19-47.
doi: 10.2147/ceg.s4343. Epub 2008 Dec 16.

Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

Claire M Payne  1 , Carol Bernstein, Katerina Dvorak, Harris Bernstein
Affiliations

Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

Claire M Payne et al. Clin Exp Gastroenterol. 2008.

Abstract

Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

Keywords: bile acids; colon cancer; genomic instability.

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Figures

Figure 1
Figure 1
The primary bile acids, cholic acid and chenodeoxycholic acid, are formed in the liver from cholesterol and conjugated, usually with glycine or taurine. They are then secreted into the gall bladder. From the gall bladder, glyco-and tauro- conjugated primary bile acids are released into the duodenum to aid in the digestion of fats. In the terminal ileum and in the cecum, the primary bile acids are deconjugated. Further, in the cecum, they are dehydroxylated through the action of bacterial 7-alpha dehydroxylases. By this reaction, cholic acid and chenodeoxycholic acid are converted to the more genotoxic-hydrophobic bile acids deoxycholic acid and lithocholic acid, respectively.
Figure 2
Figure 2
Schematic diagram indicating some of the hydrophobic bile acid (HBA)-induced signaling pathways that begin with the activation of surface enzymes, the subsequent generation of ROS, and the resultant stresses/damages that, if excessive, result in cell death. The most well documented deleterious effects of HBAs in colon cells are DNA damage, mitochondrial stress and ER stress. DNA damage results in the activation of mitotic checkpoint proteins leading to growth arrest. Mitochondrial damage results in the activation of caspases and the cleavage of multiple substrates in the cell. ER stress activates several pro-apoptotic molecules that result in cell death. Repair processes responsive to DNA damage, mitochondrial stress and ER stress can deplete the energy reserves of the cell, resulting in “metabolic stress”. Too much stress on the cell results in cell death through mechanisms that involve apoptosis, necrosis, and/or autophagy. HBA-induced mitotic stress can lead to abnormal cell division. Excessive mitotic stress may lead to mitotic catastrophe and cell death, although the details of this mode of cell death have not been well described. Necrotic cells induced by HBA may, especially, elicit an inflammatory response in vivo, and this could explain, in part, the induction of colitis by chronic feeding of HBA in mouse models. See text for details. Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; PKC, protein kinase C; PLA2, phospholipase A2; LOX, lipoxygenase; ROS, reactive oxygen species; XO, xanthine oxidase.
Figure 3
Figure 3
Schematic diagram illustrating a probable sequence of events resulting from exposure to high levels of hydrophobic bile acids (HBAs) that accompany a high-fat diet. This exposure leads to HBA-induced generation of ROS/RNS, activation of survival pathways (eg, autophagy, NF-κB), the generation of cells with genomic instability (eg, mutations, aneuploidy) and clonal selection of mutant cells with survival and proliferative advantages. The end results are the production of adenomas that progress to colon cancer. The epithelial cells of the colon of a person on a Western-style (high-fat/low vegetable/low micronutrient) diet are probably in a persistant “war zone” (bombardment with HBA-induced ROS/RNS, presence of food carcinogens, toxins, etc.). Cells in different stages of progression to malignancy are thus persistently receiving damages to their genome, resulting in clones of cells that are selected for survival in the adverse environment of the colon. While cells in the previous population, if receiving excessive DNA damage, underwent cell death altruistically for the overall benefit of the organism, the new clones of cells may behave selfishly. The new clones may acquire resistance to apoptosis and undergo clonal selection on the basis of their survival advantage, even when their DNA is damaged and after their genomes become unstable. This allows progression to adenomas and colon cancer. Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; PLA2, phospholipiase A2; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.
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