Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice.
Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor/lymphoid enhancer factor complex has been considered crucial for the initiation of intestinal tumorigenesis. The human multidrug resistance (MDR)1 (ABCB1) gene contains multiple beta-catenin-T-cell factor4-binding elements in its promoter and is one of the immediate targets of the complex. In the current study, we have further substantiated the biological involvement of MDR1 in intestinal tumorigenesis based on the following evidence: (a) aberrant induction of the Mdr1a (Abcb1a) gene product, P-glycoprotein, associated with nuclear accumulation of the beta-catenin protein, was observed even in nascent microscopic adenomas of Min mice; (b) Mdr1-deficient Min (Apc(Min/+)Mdr1a/b(-/-)) mice developed significantly fewer intestinal polyps than did Apc(Min/+)Mdr1a/b(+/+) mice; and (c) Inhibitors of P-glycoprotein, verapamil, and cyclosporin A had a suppressive effect on the in vitro polypoid growth of IEC6 expressing stabilized (DeltaN89) beta-catenin protein. Inhibitors of P-glycoprotein may be included in a novel class of chemopreventive agents against colorectal carcinogenesis.
Yamada
Tesshi
T
Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan. tyamada@gan2.res.ncc.go.jp
Mori
Yasuharu
Y
Hayashi
Reiko
R
Takada
Mizuho
M
Ino
Yoshinori
Y
Naishiro
Yasuyoshi
Y
Kondo
Tadashi
T
Hirohashi
Setsuo
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D018014:Gene Transfer Techniques; D017491:Genes, APC / Q000502:physiology*; D019450:Genes, MDR / Q000235:genetics*; D018095:Germ-Line Mutation; D007417:Intestinal Polyps / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014700:Verapamil / Q000494:pharmacology; D051176:beta Catenin
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D016572:Cyclosporine; D014700:Verapamil