Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers

• Published in: Molecular cancer Vol. 9; no. 1; p. 310
• Main Authors: Saifo, Maher S, Rempinski, Jr, Donald R, Rustum, Youcef M, Azrak, Rami G
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02-12-2010; BioMed Central; BMC
• Subjects: Antineoplastic Agents - pharmacology; beta Catenin - genetics; beta Catenin - metabolism; Blotting, Western; Cancer; Cancer therapies; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cloning; Colorectal cancer; Cytoplasm; Cytotoxicity; Drug therapy; Etiquette; Free radicals; Health aspects; Humans; Kinases; Mutation; Neoplasms - metabolism; Organoplatinum Compounds - pharmacology; Organoselenium Compounds - pharmacology; Paclitaxel - pharmacology; Patient outcomes; Physiological aspects; RNA Interference; Selenium; Standard deviation; Taxoids - pharmacology; Topotecan - pharmacology; United States; Syria
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-9-310

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.
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.
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.