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

J M Bugni1, L B Meira, L D Samson

  • 1Biological Engineering Department and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Oncogene
|November 26, 2008
PubMed

Insights

O(6)-methylguanine DNA methyltransferase (MGMT) loss contributes to colorectal cancer. Mgmt deficiency exacerbates DNA damage from alkylating agents, increasing tumor risk, especially when combined with mismatch repair defects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • O(6)-methylguanine DNA methyltransferase (MGMT) repairs DNA alkylation damage.
  • Loss of MGMT expression via epigenetic silencing is common in human cancers, including colorectal cancer.
  • MGMT's role in colorectal cancer development, particularly in response to alkylating agents, requires further investigation.

Purpose of the Study:

  • To investigate the protective role of Mgmt against chemically induced colorectal cancer in a mouse model.
  • To determine the impact of Mgmt deficiency on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) and adenomas.
  • To examine the genetic interaction between Mgmt and Msh6 (DNA mismatch repair) in colorectal tumorigenesis.

Main Methods:

  • Utilized genetically engineered mice with a targeted disruption of the Mgmt gene.
  • Administered azoxymethane (AOM) and dextran sulfate sodium (DSS) to induce colorectal tumors.
  • Assessed the formation of aberrant crypt foci (ACF) and adenomas in the colon.
  • Investigated the combined effects of Mgmt and Msh6 null mutations.

Main Results:

  • Mgmt deficiency significantly increased AOM-induced ACF and AOM/DSS-induced adenoma formation.
  • Combined Mgmt and Msh6 deficiency showed a multiplicative effect on ACF formation, linked to suppressed alkylation-induced apoptosis.
  • Mgmt deficiency did not influence spontaneous intestinal adenoma development in Apc(Min/+) mice.

Conclusions:

  • Mgmt plays a critical role in suppressing colorectal cancer development induced by exogenous alkylating agents.
  • The loss of Mgmt function exacerbates DNA damage and promotes tumorigenesis.
  • Endogenous alkylation does not appear to be a major driver of spontaneous intestinal adenomas in Apc(Min/+) mice.

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