Abstract
Demethylincisterol A3 (Sdy-1), a highly degraded sterol that we previously isolated from Chinese mangrove Rhizophora mucronata endophytic Pestalotiopsis sp. HQD-6, exhibits potent antitumor activity towards a variety of cancer cells. In this study, we further verified that Sdy-1 effectively inhibited the proliferation and migration of human liver (HepG2) and cervical cancer (HeLa) cells in vitro and it can induce cell apoptosis and arrest the cell cycle in the G1-phase. Mechanistically, we demonstrated that Sdy-1 executes its function via inhibition of the Wnt/β-catenin signaling pathway. Sdy-1 may not inhibit the Wnt signaling pathway through the cascade reaction from upstream to downstream, but directly acts on β-catenin to reduce its transcription level, thereby reducing the level of β-catenin protein and further reducing the expression of downstream related proteins. The possible interaction between Sdy-1 and β-catenin protein was further confirmed by molecular docking studies. In the nude mouse xenograft model, Sdy-1 can also significantly inhibit tumor growth. These results indicated that Sdy-1 is an efficient inhibitor of the Wnt signaling pathway and is a promising antitumor candidate for therapeutic applications.
Highlights
IntroductionThe Wnt signaling pathway plays an essential role in various cellular responses and oncogenesis, including cell morphology, proliferation, motility, and differentiation [1,2]
The Wnt signaling pathway plays an essential role in various cellular responses and oncogenesis, including cell morphology, proliferation, motility, and differentiation [1,2].β-catenin is a key component of the Wnt signaling pathway and acts as a coactivator for transcription factors of the T-cell factor / lymphoid- enhancing (TCF/lymphoid enhancer-binding factor (LEF)) family [3], and the bulk of β-catenin content in the cell is modulated by β-catenin protein stabilization.A complex of scaffolding protein Axin, glycogen synthase kinase-3β (GSK3β), and adenomatous polyposis coli (APC) protein in the cytoplasm (Axin/GSK3β/APC) catalyzes β-catenin phosphorylation and sequentially leads to its recognition of ubiquitin-dependent proteasomal degradation in normal cells
The results showed that Sdy-1 inhibited the level lation of β-catenin in the nucleus, which further confirmed the inhibition of of β-catenin in the cytoplasm and nuclear lysate of two kinds of tumor cells
Summary
The Wnt signaling pathway plays an essential role in various cellular responses and oncogenesis, including cell morphology, proliferation, motility, and differentiation [1,2]. Axin complex induces unphosphorylated β-catenin, which is stabilized in the cytoplasm to translocate into the nucleus where it forms complexes with T-cell transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) These complexes activate transcription of Wnt downstream regulatory genes, including Cyclin D1, CDK4, c-myc, and related genes [6]. Chemical investigation of HQD-6 led to the isolation of a highly degraded sterol, demethylincisterol A3 (Sdy-1), its structure was unequivocally determined by extensive NMR spectroscopic experiments as well as mass spectrometry (Figures S1–S8) and comparison with data reported in the literature [28,29] It was first reported as a synthetic intermediate in the synthesis of 17-methylincisterol and was isolated from different kinds of edible and medicinal mushrooms and marine sponges [29,30,31]. We studied the specific mechanism of action of Sdy-1 and found evidence that Sdy-1 reduces the viability of HepG2 and HeLa cells by inhibiting the Wnt signaling pathway
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