Abstract
Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/β-catenin signaling pathway. Physalis peruviana-derived 4βHWE showed a significant inhibitory activity with a calculated IC50 of 0.09 μΜ in a screening of novel inhibitors of Wnt signaling with the dual-luciferase reporter assay. This study investigated the anti-tumor effect of 4βHWE and the potential Wnt signaling inhibitory mechanism. Both the western blot analysis and immunofluorescence assay showed that 4βHWE promoted the phosphorylation and degradation of β-catenin and the subsequent inhibition of its nuclear translocation to attenuate the endogenous Wnt target gene expression in colorectal cancer (CRC) cells. The cell viability assay indicated that 4βHWE preferentially inhibited the proliferation of CRC compared with CCD-841-CoN, a normal human colonic epithelial cell line. 4βHWE-mediated G0/G1 cell cycle arrest and apoptosis induction contributed to the suppression of the proliferation of CRC in the cell cycle and Annexin V-FITC/Propidium Iodide apoptosis analysis. Moreover, in vivo, 4βHWE dramatically inhibited tumor growth in HCT116 xenografts by attenuating the Wnt/β-catenin signaling pathway. In conclusion, our study suggested that 4βHWE could be of potential use in anti-tumor agent development as a novel Wnt signaling inhibitor.
Highlights
The highly evolutionarily conserved Wnt/β-catenin signaling pathway is integral in embryonic development, the regeneration of tissues in adult organisms, stem cell differentiation, and tissue homeostasis, as well as many other biological processes [1]
The accumulation of β-catenin leads to its nuclear translocation and complex formation with the transcription factors, T-cell factor (TCF)/Lymphoid enhancer-binding factor (LEF), in the nucleus to regulate the expression of proteins required for cell proliferation and survival, such as cyclin
We explored the effect of 4β-Hydroxywithanolide E (4βHWE) on Wnt signaling and the growth of colorectal cancer (CRC) cells
Summary
The highly evolutionarily conserved Wnt/β-catenin signaling pathway is integral in embryonic development, the regeneration of tissues in adult organisms, stem cell differentiation, and tissue homeostasis, as well as many other biological processes [1]. The core of the Wnt signaling pathway is the degradation of the transcription co-factor β-catenin mediated by the destruction complex, consisting of Axin, casein kinase 1 (CK1), glycogen synthase kinase-3β (GSK-3β), and adenomatous polyposis coli (APC). Several natural dietary compounds have been suggested as promising alternative options for their ability to inhibit cancers by suppressing the Wnt/β-catenin signaling pathway, such as Genistein, Epigallocatechin gallate, Curcumin, and Resveratrol [8]. 4β-Hydroxywithanolide E (4βHWE) is a natural withanolide with a 17α-oriented side chain [11,12], exhibiting anti-inflammatory effects in diabetic mouse adipose tissue [13] by attenuating NF-κB signaling and obvious anti-tumor activity against various cancer cells [14,15,16,17,18,19].
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