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Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice.
Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice.
- Source :
-
Cancer research [Cancer Res] 2003 Mar 01; Vol. 63 (5), pp. 895-901. - Publication Year :
- 2003
-
Abstract
- 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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis
ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
Animals
Cell Division drug effects
Cyclosporine pharmacology
Cytoskeletal Proteins biosynthesis
Cytoskeletal Proteins genetics
Gene Transfer Techniques
Germ-Line Mutation
Intestinal Polyps drug therapy
Intestinal Polyps metabolism
Intestinal Polyps pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Rats
Trans-Activators biosynthesis
Trans-Activators genetics
Verapamil pharmacology
beta Catenin
Genes, APC physiology
Genes, MDR genetics
Intestinal Polyps genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 63
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 12615699