Physalis peruviana-Derived 4β-Hydroxywithanolide E, a Novel Antagonist of Wnt Signaling, Inhibits Colorectal Cancer In Vitro and In Vivo

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.

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

“…Ye et al have recently reported that 4β-hydroxywithanolide E (4β-HWE), a natural withanolide from Physalis peruviana increases the level of phosphorylated β-catenin and decreases the levels of active nonphosphorylated form and total β-catenin in colon cancer HCT116 cells ( Ye et al., 2019 ). 4β-HWE has been shown to inhibit cell viability and induce cell cycle arrest at the G0/G1 phase and apoptosis in colon cancer cells with minimal cytotoxicity against normal colonic epithelial cells (CCD-841-CoN) ( Ye et al., 2019 ). More importantly, this compound has shown potent inhibitory effects on tumor growth in mice bearing HCT116 xenograft tumors, without causing significant changes in the average body weights of mice ( Ye et al., 2019 ).…”

“…4β-HWE has been shown to inhibit cell viability and induce cell cycle arrest at the G0/G1 phase and apoptosis in colon cancer cells with minimal cytotoxicity against normal colonic epithelial cells (CCD-841-CoN) ( Ye et al., 2019 ). More importantly, this compound has shown potent inhibitory effects on tumor growth in mice bearing HCT116 xenograft tumors, without causing significant changes in the average body weights of mice ( Ye et al., 2019 ). Wei et al have found that ethanol extract of Scutellaria barbata D. Don (EESB) inhibits the viability and proliferation of colon cancer HT-29 cells in vitro and suppresses the growth of HT-29 xenograft tumors in vivo ( Wei et al., 2017 ).…”

Phytochemicals targeting metabolic reprogramming in cancer: an assessment of role, mechanisms, pathways and therapeutic relevance

“…In vivo as well as in vitro studies shows that Physalis peruviana-Derived 4-Hydroxywithanolide E-a natural withanolide and umbelliprenin alters the Wnt signaling by reducing the protein expression of Wnt-2, β-catenin, GSK-3β, p-GSK-3β, Survivin and c-myc. It also inhibits the translocation of β-catenin into the nucleus in colorectal and gastric cancer respectively [258]. Silibinin also inhibits the β-catenin levels and its translocation inside the nucleus in colorectal cancer [259].…”

Golden berry 4β-hydroxywithanolide E prevents tumor necrosis factor α-induced procoagulant activity with enhanced cytotoxicity against human lung cancer cells

“…Previous studies have shown that 4HW has cytotoxic effect against human lung, breast, oral, pancreatic, prostate and renal cancer lines in vitro [24][25][26][27][28] . 4HW also inhibited tumor growth in mouse xenograft models of liver and colorectal cancer 29,30 . Besides anticancer effects, low-dose 4HW exhibits potent anti-inflammatory activity in vitro and in vivo through inhibiting NF-κB or Akt signaling [31][32][33] .…”