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Fucose-containing fraction of Ling-Zhi enhances lipid rafts-dependent ubiquitination of TGF? receptor degradation and attenuates breast cancer tumorigenesis.

ABSTRACT: Ganoderma lucidum exerts antitumor activity, but the mechanism of G. lucidum polysaccharides on cancer is unclear. Here, we demonstrated that a fucose-containing fraction of Ling-Zhi (FFLZ) reduced tumor size and suppressed metastasis in vivo. Furthermore, FFLZ inhibited breast cancer cell migration and altered the epithelial-to-mesenchymal transition (EMT) phenotype. Transforming growth factor-? receptor (TGFR) pathways act as key mediators to promote tumor progression and metastasis. We found that FFLZ down-regulated TGFR and downstream signaling pathways, including the phosphorylation of Smad2/3 and the expression of Smad4. In an investigation of the underlying mechanisms, we found that FFLZ enhanced the Smurf2-dependent ubiquitination of TGFR by disrupting the balance of the lipid rafts, promoted the "re-localization" of the TGFR to the caveolae, and facilitated the degradation of TGFR. Together, our data indicated that FFLZ is associated with the inhibition of EMT and the prevention of metastasis by promoting ubiquitination-dependent TGFR degradation and abolishing TGFR signaling pathways. Moreover, the combination of FFLZ and trastuzumab synergistically inhibited the viability of certain trastuzumab-resistant human breast cancer cells. In summary, our current findings indicate that FFLZ is a potential therapeutic or dietary supplemental agent for cancer patients and that it functions via the caveolin-1/Smad7/Smurf2-dependent ubiquitin-mediated degradation of TGFR.

SUBMITTER: Tsao SM

PROVIDER: S-EPMC5103195 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Fucose-containing fraction of Ling-Zhi enhances lipid rafts-dependent ubiquitination of TGFβ receptor degradation and attenuates breast cancer tumorigenesis.

Tsao Shu-Ming SM Hsu Hsien-Yeh HY

Scientific reports 20161110

Ganoderma lucidum exerts antitumor activity, but the mechanism of G. lucidum polysaccharides on cancer is unclear. Here, we demonstrated that a fucose-containing fraction of Ling-Zhi (FFLZ) reduced tumor size and suppressed metastasis in vivo. Furthermore, FFLZ inhibited breast cancer cell migration and altered the epithelial-to-mesenchymal transition (EMT) phenotype. Transforming growth factor-β receptor (TGFR) pathways act as key mediators to promote tumor progression and metastasis. We found ...[more]

PMID: 27830743

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Project description:Varicocele (VC) is a common urogenital disease that leads to a high risk of testicular pain or male infertility. The purpose of this research was to explore the molecular mechanism of the Gui Zhi Fu Ling Wan (GFW) in the treatment of VC. The main active ingredients and targets information of GFW were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the targets related to VC were determined by GeneCards, Online Mendelian Inheritance in Man (OMIM), and Disease Gene Network (DisGeNET) databases. The intersection of active ingredient targets and disease targets was selected to construct a protein-protein interaction (PPI) network through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Based on the use of CytoNCA plug-in to find the main targets, a 'component-target-disease' network was constructed by Cytoscape 3.8.2. Metascape was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of drug and disease targets. Molecular docking was employed to investigate the binding interaction between the main active components and core targets. A total of 76 active components of GFW were screened out. The main targets of the active components on VC were tumour protein p53 (TP53), tumour necrosis factor (TNF), hypoxia inducible factor 1 subunit alpha (HIF1A), interleukin-6 (IL-6), caspase 3 (CASP3), catalase (CAT), prostaglandin-endoperoxide synthase 2 (PTGS2), vascular endothelial growth factor A (VEGFA). The PI3K-Akt signalling pathway, HIF-1 signalling pathway, and apoptosis signalling pathway were mainly involved in the regulation of VC. The results of molecular docking showed that the binding potential and activity of the main active components and the core targets of GFW were good. We found that GFW could alleviate apoptosis, participate in venous vessel morphogenesis, and reduce oxidative stress in the treatment of VC. This study can provide a reference for subsequent clinical and scientific research experiments, which can be used to design new drugs and develop new therapeutic instructions to treat VC.

Dataset Information

Fucose-containing fraction of Ling-Zhi enhances lipid rafts-dependent ubiquitination of TGF? receptor degradation and attenuates breast cancer tumorigenesis.

Publications

Fucose-containing fraction of Ling-Zhi enhances lipid rafts-dependent ubiquitination of TGFβ receptor degradation and attenuates breast cancer tumorigenesis.

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