OncoTargets and Therapy (Feb 2016)
Arsenic trioxide inhibits viability and induces apoptosis through reactivating the Wnt inhibitor secreted frizzled related protein-1 in prostate cancer cells
Abstract
Lei Zheng,1,2 Hui Jiang,3 Zhi-Wei Zhang,1 Ke-Nan Wang,1 Qi-Fei Wang,1 Quan-Lin Li,1 Tao Jiang1 1Department of Urology, First Affiliated Hospital of Dalian Medical University, 2Department of Urology, The Fifth People’s Hospital of Dalian, Dalian, 3Department of Urology, Third Affiliated Hospital of Beijing University, Beijing, People’s Republic of China Background: Growing evidence suggests that arsenic trioxide (As2O3) induces apoptosis and inhibits tumor cell growth in prostate cancer (PCa), although details of the mechanism are still inconclusive. We investigated the antitumor effect of As2O3 in human PCa cell lines LNCaP and PC3 and the underlying mechanisms by focusing on the Wnt signaling pathway.Methods: The effect of As2O3 on the viability and apoptosis of PCa cells was investigated by cholecystokinin-8 and flow cytometry. The expression of the related proteins in the Wnt signaling pathway and the downstream target genes of the Wnt signaling pathway was examined by Western blot and quantitative real-time PCR assay. The methylation status of the SFRP1 gene promoter was assessed by bisulfite sequencing.Results: As2O3 inhibited the viability of PCa cells and induced apoptosis of PCa cells in a dose-dependent manner. The protein level of phospho-glycogen synthase kinase-3β was upregulated, whereas the protein level of β-catenin and the mRNA levels of c-MYC, MMP-7, and COX-2 were downregulated in a dose-dependent manner in PCa cells treated with As2O3. In addition, As2O3 pregulated the protein and mRNA levels of secreted frizzled related protein-1, and increased the demethylation of the SFRP1 gene promoter.Conclusion: Our results suggest that As2O3 may inhibit cell viability and induce apoptosis through reactivating the Wnt inhibitor secreted frizzled related protein-1 in both androgen-dependent and -independent human PCa. Keywords: arsenic trioxide, CpG island methylation, demethylation, prostate cancer, Wnt signaling pathway, SFRP1
