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

Payne CM, Bernstein C, Dvorak K, Bernstein H - Clin Exp Gastroenterol (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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f2-ceg-1-019: 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.

Mentions: Sporadic colon cancer is caused predominantly by dietary factors, most notably a high-fat diet accompanied by low intake of micronutrients (folate, niacin, zinc), antioxidants and other plant phytochemicals. A high intake of fat induces the release of bile acids from the gall bladder into the small intestine. Bacteria in the colonic lumen then convert conjugated and hydrophilic bile acids to unconjugated, hydrophobic bile acids such as deoxycholic acid and lithocholic acid (Figure 1). These hydrophobic bile acids, deoxycholic acid in particular, have been reported to be multiple stress inducers and at high physiologic levels can create chaos within colon epithelial cells. These stresses include membrane perturbation, oxidative DNA damage, decrease in DNA repair proteins, mitotic stress, micronuclei formation, mitochondrial damage (metabolic stress) and endoplasmic reticulum (ER) stress (Figure 2).


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

Payne CM, Bernstein C, Dvorak K, Bernstein H - Clin Exp Gastroenterol (2008)

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.
© Copyright Policy
Related In: Results  -  Collection

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f2-ceg-1-019: 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.
Mentions: Sporadic colon cancer is caused predominantly by dietary factors, most notably a high-fat diet accompanied by low intake of micronutrients (folate, niacin, zinc), antioxidants and other plant phytochemicals. A high intake of fat induces the release of bile acids from the gall bladder into the small intestine. Bacteria in the colonic lumen then convert conjugated and hydrophilic bile acids to unconjugated, hydrophobic bile acids such as deoxycholic acid and lithocholic acid (Figure 1). These hydrophobic bile acids, deoxycholic acid in particular, have been reported to be multiple stress inducers and at high physiologic levels can create chaos within colon epithelial cells. These stresses include membrane perturbation, oxidative DNA damage, decrease in DNA repair proteins, mitotic stress, micronuclei formation, mitochondrial damage (metabolic stress) and endoplasmic reticulum (ER) stress (Figure 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA.

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.

No MeSH data available.


Related in: MedlinePlus