The effect of selenium on the oncogenic protein β-catenin in human colorectal cancers.

Abstract

e13553 Background: β-catenin is a multifunctional oncogenic protein leads to many types of human cancers by affecting cell growth and adhesion. Recently, Wnt/β-catenin signaling pathway is implicated in the self-renewal of stem cells. Cancer stem cells (CSCs) contribute to tumor bulk, recurrence and resistance to chemotherapy. In colorectal carcinomas, Wnt/β-catenin signaling pathway is activated due to a mutation in the tumor suppresser gene, APC. This study is to determine whether pharmacological doses of a selenium-containing compound, methylseleninic acid (MSeA), have an effect on the expression of β-catenin in colorectal carcinomas. Methods: Two human colorectal cancer cell lines, HCT-8 and HT-29,were treated with MSeA alone, SN-38 alone (the active metabolite of irinotecan, a topoisomearse I inhibitor) and in sequential combination of MSeA/SN-38. MSeA was applied at various doses and exposure times. SN-38 was used at concentration that inhibits 50% of cell growth. After treatments, the effect on intracellular level of β-catenin was detected using western blot analyses. The effect on cell growth/death was measured using Sulforhodamine B (SRB) assay. Results: Untreated HCT-8 and HT-29 cells expressed β-catenin. MSeA inhibited intracellular level of β-catenin in dose and time dependent manners. The reduced level of β-catenin after MSeA treatments was associated with inhibition of tumor cell growth and enhancement of cell death. SN-38 alone had no effect onβ-catenin level. The sequential combination of MSeA/SN-38 resulted in more inhibition of β-catenin when compared to all other treatment groups. Conclusions: In colorectal carcinomas, MSeA is a potent inhibitor of β-catenin that consequently led to cell growth inhibition and death. Sequential combination of MSeA/SN-38 resulted in further increase in β-catenin inhibition, thus offering the potential for reversal of drug resistance and tumor relapse. Based on these results and given the important role of Wnt/β-catenin signaling pathway in CSCs, MSeA is an excellent candidate regimen for future therapeutic combinations to reduce tumor bulk, reverse drug resistance and eradicate CSCs, thus preventing tumor relapse and increasing cure rates. No significant financial relationships to disclose.