Dataset Information

Wnt-?-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer.

ABSTRACT: We determined the gene expression profiles for 48 ATP binding cassette (ABC) transporters in matched colon cancer and normal colon tissues in order to provide insight into the mechanisms underlying expression of transporters related to colon carcinogenesis. The expression of ABCB1, ABCC1, ABCC2, ABCC3, and ABCG2 was altered in association with colon carcinogenesis. Among these transporters, the expression of ABCC3 was repressed by Wnt signaling pathway in colon cancer cell lines. Knockdown of the pathway components transcription factor 7-like 2 (TCF7L2) or ?-catenin thus increased ABCC3 expression, whereas activation of Wnt signaling with inhibitors of glycogen synthase kinase-3? (GSK-3?) reduced it. ChIP and luciferase reporter assays also showed that TCF7L2 binds to the ABCC3 locus and regulates its expression. Finally, overexpression of ABCC3 in colon cancer cells conferred resistance to anticancer drug-induced cytotoxicity. Our data thus suggest that Wnt signaling represses ABCC3 expression during colon carcinogenesis, and that subsequent upregulation of ABCC3 expression during drug treatment might contribute to acquired drug resistance.

SUBMITTER: Kobayashi M

PROVIDER: S-EPMC5198960 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Wnt-β-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer.

Kobayashi Minoru M Funayama Ryo R Ohnuma Shinobu S Unno Michiaki M Nakayama Keiko K

Cancer science 20161213 12

We determined the gene expression profiles for 48 ATP binding cassette (ABC) transporters in matched colon cancer and normal colon tissues in order to provide insight into the mechanisms underlying expression of transporters related to colon carcinogenesis. The expression of ABCB1, ABCC1, ABCC2, ABCC3, and ABCG2 was altered in association with colon carcinogenesis. Among these transporters, the expression of ABCC3 was repressed by Wnt signaling pathway in colon cancer cell lines. Knockdown of th ...[more]

PMID: 27709738

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Project description:It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify ?-catenin as a primary necessary protein. Alcohol increases ?-catenin, and blocking accumulation of ?-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/?-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/?-catenin reduces BK current density. A point mutation in a putative glycogen synthase kinase phosophorylation site within the S10 region of BK blocks internalization, suggesting that Wnt/?-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/?-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity.Alcohol tolerance is a key step toward escalating alcohol consumption and subsequent dependence. Our research aims to make significant contributions toward novel, therapeutic approaches to prevent and treat alcohol misuse by understanding the molecular mechanisms of alcohol tolerance. In our current study, we identify the role of a key regulatory pathway in alcohol-induced persistent molecular changes within the hippocampus. The canonical Wnt/?-catenin pathway regulates BK channel surface expression in a protein synthesis-dependent manner reminiscent of other forms of long-term hippocampal neuronal adaptations. This unique insight opens the possibility of using clinically tested drugs, targeting the Wnt/?-catenin pathway, for the novel use of preventing and treating alcohol dependency.

Dataset Information

Wnt-?-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer.

Publications

Wnt-β-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer.

Similar Datasets

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