High susceptibility of Scid mice to colon carcinogenesis induced by azoxymethane indicates a possible caretaker role for DNA-dependent protein kinase.
Severe combined immunodeficiency (Scid) mice have defects in V(D)J recombination and DNA double-strand breaks repair caused by an inherited genetic defect in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Scid mice are highly susceptible to development of T-cell lymphomas, and because of the nature of its association with DNA repair and recombination, DNA-PKcs is considered to belong to the caretaker class of tumor suppressor genes. In the present study, the susceptibility of Scid mice to colon carcinogenesis due to administration of azoxymethane (AOM) was investigated. Significantly higher susceptibility in terms of induction of both aberrant crypt foci (ACFs), putative pre-cancerous lesions of the colon and colon cancers was observed as compared with the isogenic strain, C.B-17 mice. The incidences of colon tumors, either adenomas or adenocarcinomas, in Scid and C.B-17 mice after administration of AOM (10 mg/kg body weight/week) for 6 weeks were 87% (26 of 30) and 50% (15 of 30), respectively, by experimental week 22 (P < 0.01). The multiplicity of colon tumors in Scid mice was also significantly higher than in C.B-17 mice, being 2.2 +/- 1.5 and 0.9 +/- 1.2, respectively (P < 0.001). The present study clearly demonstrated high susceptibility of Scid mice to colon carcinogenesis, which might be attributable to disruption of the caretaker role of DNA-PK in colonic epithelial cells.
Ochiai
M
M
Biochemistry Division and Cancer Prevention Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, Japan.
Ubagai
T
T
Kawamori
T
T
Imai
H
H
Sugimura
T
T
Nakagama
H
H
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D011230:Precancerous Conditions / Q000139:chemically induced; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D051176:beta Catenin; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D001397:Azoxymethane