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Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice
Tesshi Yamada1, Yasuharu Mori, Reiko Hayashi
1Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan. tyamada@gan2.res.ncc.go.jp
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.
Insights
Multidrug resistance (MDR)1 gene product P-glycoprotein is involved in intestinal tumor initiation. MDR1 deficiency reduced polyp formation in mice, suggesting P-glycoprotein inhibitors could prevent colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant activation of the beta-catenin/T-cell factor (TCF) complex drives intestinal tumorigenesis.
- The human multidrug resistance (MDR)1 (ABCB1) gene is a direct target of this complex, containing TCF-binding elements in its promoter.
Purpose of the Study:
- To investigate the role of MDR1 and its product P-glycoprotein in intestinal tumorigenesis.
- To evaluate the potential of P-glycoprotein inhibitors as chemopreventive agents for colorectal cancer.
Main Methods:
- Examined P-glycoprotein and beta-catenin expression in nascent intestinal adenomas of Min mice.
- Compared intestinal polyp development in Mdr1-deficient Min mice versus control mice.
- Assessed the effect of P-glycoprotein inhibitors (verapamil, cyclosporin A) on in vitro polypoid growth of cancer cells.
Main Results:
- P-glycoprotein was aberrantly induced in microscopic adenomas, correlating with nuclear beta-catenin accumulation.
- Mdr1-deficient mice developed significantly fewer intestinal polyps than controls.
- P-glycoprotein inhibitors suppressed in vitro polypoid growth of cells with stabilized beta-catenin.
Conclusions:
- MDR1 and its product P-glycoprotein play a significant role in intestinal tumorigenesis.
- P-glycoprotein inhibitors show promise as a novel class of chemopreventive agents against colorectal carcinogenesis.