Intrinsic resistance to apoptosis of colon epithelial cells is a potential determining factor in the susceptibility of the A/J mouse strain to dimethylhydrazine-induced colon tumorigenesis.
Alterations in the delicate balance between cell proliferation and cell death disrupt colon homeostasis and serve as determining factors in colon tumorigenesis. The two mouse strains, AKR/J (resistant) and A/J (susceptible), have been widely used as models for dimethylhydrazine-induced colon tumorigenesis. This study examined whether the differential susceptibilities of the two mouse strains to the tumorigenic effect of dimethylhydrazine were associated with intrinsic differences in the apoptotic machinery of the colon epithelial cells. While acute exposure to dimethylhydrazine caused massive apoptosis of colon epithelial cells in AKR/J mice, the effect was considerably less in A/J mice. Apoptosis in AKR/J mice occurred not only in the luminal side of the mucosa but also deep in the colonic crypts. In addition, this apoptosis appeared to involve caspase-3. The increased sensitivity of AKR/J to dimethylhydrazine was associated with a persistent expression of tumor necrosis factor (TNF) but not of its receptors. After establishing a new method for isolating primary colon epithelial cells, we determined that cells derived from A/J mice were substantially more resistant to apoptosis in response to dimethylhydrazine or to a combination of TNF, cyclohexamide, and butyrate compared to cells from AKR/J mice. These results strongly suggest that a higher intrinsic resistance to apoptosis of colon epithelial cells may be an important determinant of predisposition to colon tumorigenesis in the A/J mouse strain.
Oumouna-Benachour
Karine
K
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Oumouna
Mustapha
M
Zerfaoui
Mourad
M
Hans
Chetan
C
Fallon
Kenneth
K
Boulares
A Hamid
AH
D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D003106:Colon / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D004198:Disease Susceptibility; D004789:Enzyme Activation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002273:Carcinogens; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D019813:1,2-Dimethylhydrazine