Hydrophobic Bile Acid-Induced Micronuclei Formation, Mitotic Perturbations, and Decreases in Spindle Checkpoint Proteins: Relevance to Genomic Instability in Colon Carcinogenesis

We show, for the first time, that hydrophobic bile acids cause aberrations of the mitotic machinery of colon cells that can give rise to aneuploidy, the chromosomal perturbations common in colon tumors. First, we show that DOC induces a statistically significant fourfold increase in the number of mi...

Full description

Saved in:
Bibliographic Details
Published in:Nutrition and cancer 2010-01, Vol.62 (6), p.825-840
Main Authors: Payne, Claire M, Crowley-Skillicorn, Cheray, Bernstein, Carol, Holubec, Hana, Moyer, Mary Pat, Bernstein, Harris
Format: Article
Language:English
Subjects:
Bile
Biological and medical sciences
carcinogenesis
Cell division
Cell Line, Tumor
Cells
Chromosomes
Colonic Neoplasms - etiology
Colonic Neoplasms - genetics
Colorectal cancer
colorectal neoplasms
Cytokines
Deoxycholic Acid - toxicity
digestive physiology
epithelial cells
Feeding. Feeding behavior
Fundamental and applied biological sciences. Psychology
Genomic Instability - drug effects
genomics
human cell lines
Humans
Hydrophobic and Hydrophilic Interactions
hydrophobicity
Micronuclei, Chromosome-Defective
Mitosis - drug effects
mitotic spindle apparatus
Nocodazole - pharmacology
Spindle Apparatus - drug effects
Tumors
Vertebrates: anatomy and physiology, studies on body, several organs or systems
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:We show, for the first time, that hydrophobic bile acids cause aberrations of the mitotic machinery of colon cells that can give rise to aneuploidy, the chromosomal perturbations common in colon tumors. First, we show that DOC induces a statistically significant fourfold increase in the number of micronuclei in NCM-460 cells (a noncancerous colon cell line) and a threefold increase in the number of micronuclei in binucleated HT-29 colon cancer cells using the cytokinesis block micronucleus assay. Second, we observed mitotic aberrations after DOC treatment, including improper alignment of chromosomes at the metaphase plate, lagging chromosomes during anaphase, anaphase/telophase chromatin bridges, multipolar divisions, and formation of polynucleated cells. It was determined that there was a statistically significant threefold increase in the number of aberrant metaphases after short-term and long-term exposure of HT-29 and HCT-116 cells, respectively. Third, we showed with Western blots and immunohistochemistry that a likely basis for these mitosis-related perturbations included decreased expression of the spindle checkpoint proteins, Mad2, BubR1, and securin. Fourth, results of DOC treatment on nocodazole-challenged cells further indicated deficiencies in activation of the spindle assembly checkpoint. This study provides mechanisms by which hydrophobic bile acids can induce genomic instability in colon epithelial cells.
ISSN:0163-5581
1532-7914
DOI:10.1080/01635581003695756