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

Abstract

BackgroundBeta-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.ResultsIn 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.ConclusionsThis 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.

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

“…53 This is consistent with previous reports indicating that AEB071, at higher doses, is a direct activator of b-catenin signaling. 27,54 Moreover, treatment of B-CLL cells with higher doses of AEB071 resulted in an increase in cell survival starting at a dose of 6.25 mM (Figure 6G), which could be a reflection of our observed increase in b-catenin levels.…”

Repeated ovarian stimulation does not affect the expression level of proteins involved in cell cycle control in mouse ovaries and fallopian tubes

“…This conclusion has been further confirmed by the similar levels of β-catenin and by the absence of pAKT and p53 in FT of control and hyperstimulated groups. In humans, the abnormal activation of the PI3K/AKT pathway [34] and increased nuclear β-catenin levels have been described to occur in OC [35]. Also in mice, high-grade serous OC can arise from the FT following deletion of PTEN, a negative regulator of PI3K pathway [36].…”

Ras Regulates SCFβ-TrCP Protein Activity and Specificity via Its Effector Protein NORE1A

“…In the canonical Wnt/␤-catenin pathway, ␤-catenin is the terminal executor, serving as both a nuclear transcriptional coregulator and key component of adherens junctions (7). In the absence of Wnt ligand signaling, a multiprotein complex consisting of APC, Axin, and GSK-3␤ phosphorylates ␤-catenin.…”