Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins.
O(6)-methylguanine DNA methyltransferase (MGMT) suppresses mutations and cell death that result from alkylation damage. MGMT expression is lost by epigenetic silencing in a variety of human cancers including nearly half of sporadic colorectal cancers, suggesting that this loss maybe causal. Using mice with a targeted disruption of the Mgmt gene, we tested whether Mgmt protects against azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), against AOM and dextran sulfate sodium (DSS)-induced colorectal adenomas and against spontaneous intestinal adenomas in Apc(Min) mice. We also examined the genetic interaction of the Mgmt null gene with a DNA mismatch repair null gene, namely Msh6. Both Mgmt and Msh6 independently suppress AOM-induced ACF, and combination of the two mutant alleles had a multiplicative effect. This synergism can be explained entirely by the suppression of alkylation-induced apoptosis when Msh6 is absent. In addition, following AOM+DSS treatment Mgmt protected against adenoma formation to the same degree as it protected against AOM-induced ACF formation. Finally, Mgmt deficiency did not affect spontaneous intestinal adenoma development in Apc(Min/+) mice, suggesting that Mgmt suppresses intestinal cancer associated with exogenous alkylating agents, and that endogenous alkylation does not contribute to the rapid tumor development seen in Apc(Min/+) mice.
Bugni
J M
JM
Biological Engineering Department and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Meira
L B
LB
Samson
L D
LD
D000477:Alkylating Agents / Q000633:toxicity; D000478:Alkylation / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016264:Dextran Sulfate / Q000633:toxicity; D017491:Genes, APC / Q000502:physiology; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000477:Alkylating Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; D025521:Tumor Suppressor Proteins; D016264:Dextran Sulfate; D015254:DNA Modification Methylases; C528331:MGMT protein, mouse; D045643:DNA Repair Enzymes; D001397:Azoxymethane