Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins

Abstract

O6-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 ApcMin 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 ApcMin/+ 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 ApcMin/+ mice.

Apurinic/apyrimidinic endonuclease 1, the sensitive marker for DNA deterioration in dextran sulfate sodium-induced acute colitis

“…27 We hypothesized that the roles of APC associated with aging may be absent while DNA repair pathways associated with mucosal damage would be present in the DSS-induced acute colitis young rat model, because mutations or deficiencies in APC and MMR contribute significantly to the development of age-related or familial colonic neoplasia and sporadic or mucosal-damage-related neoplasia, respectively. 3,8,17 As expected, young rats failed to gain body weight and had loose stools after DSS treatment, resulting in significantly different growth curves (P < 0.01). Together with the histological changes associated with acute colitis, APC immunolocalization was evident in the surface epithelium and lamina propria at the end of the study.…”

“…MMR contributes to the development of both sporadic and mucosal-damage-related neoplasia. 8,[12][13][14][15][16][17][18] We were interested in the relationship between MMR and BER in preventing DNA damage against DSS-induced colitis in young rats because MYH, which is involved in BER, is also associated with the development of colorectal cancer, and its activity is modulated by MMR and APE1. 20,21 We found that APE1 and MSH2 levels increased significantly at DSS-3d and DSS-5d, respectively.…”

“…[3][4][5][6] The information available regarding the molecular and genetic pathways that result in colorectal cancer, such as tumor suppressor genes, DNA mismatch repair (MMR) genes and proto-oncogenes, has increased markedly. The specific contributing mutations in genes such as adenomatous polyposis coli (APC) [7][8][9][10][11] and MMR 8, [12][13][14][15][16][17][18] have been investigated intensively. Mutations or deficiencies in APC and MMR contribute significantly to the development of age-related or familial colonic neoplasia and sporadic or mucosal damage-related neoplasia, respectively.…”

DNA Damage Protection and Induction of Repair by Dietary Phytochemicals and Cancer Prevention: What Do We Know?

“…If O 6 MeG remains in one of the template strands the repair process will be repeated, creating a "futile repair loop". This loop will eventually result in toxic double-strand breaks leading to chromosomal aberrations, cell-cycle arrest or apoptosis (Bugni et al, 2009;Kaina et al, 2007;Kaina et al, 2010;Kondo et al, 2010). When both of these systems fail to repair, O 6 MeG results in point mutations that can possibly initiate the carcinogenic process.…”

“…Depletion of MGMT by reducing MGMT activity or decreasing gene expression can occur using a specific inhibitor O 6 -benzylguanine (BG) or through epigenetic silencing, (Eker et al, 2009). Inhibition of MGMT with BG in rats increases azoxymethane (AOM)-induced colon tumors, and transgenic e x p r e s s i o n o f M G M T i n m i c e p r o t e c t s a g a i n s t A O M -i n d u c e d aberrant crypt foci (ACF) (Bugni et al, 2009;Wali et al, 1999).…”