6 research outputs found
Attenuated Salmonella typhimurium cancer therapy has direct effects on the tumor epithelium in colorectal cancer
Bacterial cancer therapy in autochthonous colorectal cancer affects tumor growth and metabolic landscape
Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT in xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epitheliumâtargeted mechanisms of BCT by using autochthonous mouse models of intestinal cancer and tumor organoid cultures to assess the effectiveness and consequences of oral treatment with aromatase Aâdeficient STm (STm(Î)aroA). STm(Î)aroA delivered by oral gavage significantly reduced tumor burden and tumor load in both a colitis-associated colorectal cancer (CAC) model and in a spontaneous Apc(min/+) intestinal cancer model. STm(Î)aroA colonization of tumors caused alterations in transcription of mRNAs associated with tumor stemness, epithelial-mesenchymal transition, and cell cycle. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STm(Î)aroA-treated tumors, suggesting that STm(Î)aroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro recapitulated effects seen on tumor stemness, mesenchymal markers, and altered metabolome. Furthermore, live STm(Î)aroA was required, demonstrating active mechanisms including metabolite usage. We have demonstrated that oral BCT is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium affecting tumor stem cells
Back Cover: Bicyclic βâSheet Mimetics that Target the Transcriptional Coactivator βâCatenin and Inhibit Wnt Signaling (Angew. Chem. Int. Ed. 25/2021)
Protein complexes are defined by the three-dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of proteinâprotein interactions (PPIs). Even though β-sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure-based design of β-sheet mimetics targeting the intracellular protein β-catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β-catenin, a macrocyclic peptide was designed and its crystal structure in complex with β-catenin obtained. Using this structure, we designed a library of bicyclic β-sheet mimetics employing a late-stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β-catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β-sheet-mediated PPIs
Bicyclic β-sheet mimetics that target the transcriptional coactivator βâcatenin and inhibit Wnt signaling
Protein complexes are defined by the three-dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied e.g. as inhibitors of protein-protein interactions (PPIs). Even though β-sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure-based design of β-sheet mimetics targeting the intracellular protein β-catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β-catenin, a macrocyclic peptide was designed and its crystal structure in complex with β-catenin obtained. Using this structure, we designed a library of bicyclic β-sheet mimetics employing a late-stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β-catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β-sheet-mediated PPIs