Markedly enhanced colon tumorigenesis in Apc(Min) mice lacking glutathione S-transferase Pi.

Glutathione transferases are a multigene family of proteins that catalyze the conjugation of toxic electrophiles and carcinogens to glutathione. Glutathione transferase Pi (GSTP) is commonly overexpressed in human tumors and there is emerging evidence that the enzyme has additional cellular functions in addition to its role in drug and carcinogen detoxification. To investigate the unique functions of this enzyme, we have crossed Gstp null mice with an initiated model of colon cancer, the Apc(Min) mouse. In contrast to the Apc(Min/+) Gstp1/p2(+/+) (Gstp-wt Apc(Min)) mice, which rarely develop colonic tumours, Apc(Min/+)Gstp1/p2(-/-) (Gstp-null Apc(Min)) mice had a 6-fold increase in colon adenoma incidence, and a 50-fold increase in colorectal adenoma multiplicity, relative to Gstp-wt Apc(Min). This increase was associated with early tumor onset and decreased survival. Analysis of the biochemical changes in the colon tissue of Gstp-null Apc(Min) mice demonstrated a marked induction of many inflammatory genes, including IL-6, IL-4, IFN-gamma, and inducible nitric oxide synthase. In support of the induction of inducible nitric oxide synthase, a profound induction of nitrotyrosine adducts was observed. Gstp therefore appears to play a role in controlling inflammatory responses in the colon, which would explain the change in tumor incidence observed. These data also suggest that individual variation in GSTP levels may be a factor in colon cancer susceptibility.

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