Submitted to: Biofactors
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/18/2001
Publication Date: 5/15/2001
Citation: Davis, C.D., Johnson, W.T. 2001. Dietary copper and dimethylhydrazine (DMH) affect protein kinase C (PKC) isozyme protein and MRNA expression and the formation of aberrant crypts in colon of rats. Biofactors. 15:11-26.
Interpretive Summary: Colon cancer is the second leading cause of cancer deaths in the United States and the fourth most common cause of cancer deaths worldwide. Low dietary copper has been shown to increase the risk of colon cancer development in experimental animals and to decrease the expression of various protein kinase C isozymes. Protein kinase C is a series of proteins involved in the signal transduction pathway within the cell. The current study investigated the relationship between dietary copper and carcinogen administration on protein kinase C expression and the appearance of preneoplastic lesions for colon cancer. Low dietary copper increased the formation of preneoplastic lesions for colon cancer and decreased protein kinase C expression. The current finding provides a biochemical explanation for the increased incidence of precancerous lesions in colons of copper-deficient rats when they are challenged with a carcinogen. These results have practical implications because more than 80% of the diets consumed in the United States do not contain the recommended amount of copper.
Technical Abstract: Low dietary copper has been shown to decrease the expression of various protein kinase C (PKC) isozymes and increase the risk of colon cancer development in experimental animals. Decreased expression of various PKC isozymes has also been linked to the pathogenesis of colon cancer. The purpose of this study was to investigate the relationship between dietary copper and carcinogen administration on PKC isozyme expression and aberrant crypt foci (ACF) formation in 88 weanling rats fed two concentrations of copper (0.9 and 7.7 ug/g diet) in an AIN-93 based diet. The rats were injected twice with either dimethylhydrazine (DMH)(25 mg/kg i.p.) or saline and killed at 2 time points (2 wk and 8 wk after DMH). Ingestion of low dietary copper significantly (p<0.005) increased the formation of DMH-induced ACF (116.8 vs 59.6). Western blot analysis revealed that low dietary copper significantly (p<0.05) decreased the expression of PKC alpha, delta, and zeta at 2 wk. DMH administration significantly (p<0.05) decreased the expression of PKC alpha at both time points, and decreased PKC delta, and zeta expression at 8 wk. The relative contents of PKC alpha, delta, and zeta mRNA in rat colon were measured by using rapid competitive polymerase chain reaction. In general, PKC alpha, delta, and zeta mRNA expression was not consistent with changes in protein expression. Our results demonstrate that low dietary copper increases DMH-induced aberrant crypt formation and decreases PKC alpha, delta, and zeta protein expression. Thus changes in PKC isoform protein expression may be related to increased susceptibility of copper-deficient animals to colon cancer.