Journal article
Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers
Molecular cancer, Vol.9(1), pp.310-310
12/02/2010
DOI: 10.1186/1476-4598-9-310
PMCID: PMC3014904
PMID: 21126356
Abstract
Background: Beta-catenin is a multifunctional oncogenic protein that contributes fundamentally to cell development and biology. Elevation in expression and activity of β-catenin has been implicated in many cancers and associated with poor prognosis. Beta-catenin is degraded in the cytoplasm by glycogen synthase kinase 3 beta (GSK-3β) through phosphorylation. Cell growth and proliferation is associated with β-catenin translocation from the cytoplasm into the nucleus.This laboratory was the first to demonstrate that selenium-containing compounds can enhance the efficacy and cytotoxicity of anticancer drugs in several preclinical xenograft models. These data provided the basis to identify mechanism of selenium action focusing on β-catenin as a target. This study was designed to: (1) determine whether pharmacological doses of methylseleninic acid (MSeA) have inhibitory effects on the level and the oncogenic activity of β-catenin, (2) investigate the kinetics and the mechanism of β-catenin inhibition, and (3) confirm that inhibition of β-catenin would lead to enhanced cytotoxicity of standard chemotherapeutic drugs.Results: In six human cancer cell lines, the inhibition of total and nuclear expression of β-catenin by MSeA was dose and time dependent. The involvement of GSK-3β in the degradation of β-catenin was cell type dependent (GSK-3β-dependent in HT-29, whereas GSK-3β-independent in HCT-8). However, the pronounced inhibition of β-catenin by MSeA was independent of various drug treatments and was not reversed after combination therapy.Knockout of β-catenin by ShRNA and its inhibition by MSeA yielded similar enhancement of cytotoxicity of anticancer drugs.Collectively, the generated data demonstrate that β-catenin is a target of MSeA and its inhibition resulted in enhanced cytotoxicity of chemotherapeutic drugs.Conclusions: This study demonstrates that β-catenin, a molecule associated with drug resistance, is a target of selenium and its inhibition is associated with increased multiple drugs cytotoxicity in various human cancers. Further, degradation of β-catenin by GSK-3β is not a general mechanism but is cell type dependent. © 2010 Saifo et al; licensee BioMed Central Ltd.
Details
- Title: Subtitle
- Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers
- Creators
- Maher S Saifo - Roswell Park Cancer InstituteDonald R Rempinski - Roswell Park Cancer InstituteYoucef M Rustum - Roswell Park Cancer InstituteRami G Azrak - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Molecular cancer, Vol.9(1), pp.310-310
- DOI
- 10.1186/1476-4598-9-310
- PMID
- 21126356
- PMCID
- PMC3014904
- NLM abbreviation
- Mol Cancer
- ISSN
- 1476-4598
- eISSN
- 1476-4598
- Publisher
- BioMed Central
- Language
- English
- Date published
- 12/02/2010
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359912502771
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