The fungal secondary metabolite trichodimerol inhibits TGF-β dependent cellular effects and tube formation of MDA-MB-231 cells
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The transforming growth factor-β (TGF-β) family of ligands has a pivotal role as regulators of cell growth, differentiation and migration. Overexpression of TGF-β has been associated with breast, colon, hepatocellular, lung and pancreatic cancer. Importantly, overexpression of TGF-β correlates with tumor progression, metastasis, angiogenesis and poor prognostic outcome. Therefore, TGF-β signaling has emerged as an attractive target for the development of new cancer therapeutics. In a search for metabolites from fungi inhibiting the TGF-β dependent expression of a reporter gene in HepG2 cells, we found that trichodimerol, a previously isolated bisorbicillinoid, inhibited serine phosphorylation of the TGF-β activated Smad2/3 transcription factors and antagonized the cellular effects of TGF-β including reporter gene activation and expression of TGF-β inducible genes in HepG2 and MDA-MB-231 cells. In addition, trichodimerol blocked IFN-γ, IL-6 and IL-4 induced activation of Stat1, Stat3 and Stat6 transcription factors by inhibiting serine and tyrosine phosphorylation. In an in vitro angiogenesis assay, 20 μM trichodimerol completely abrogated the capillary-like tube formation of MDA-MB-231 cells on Matrigel.
KeywordsTGF-β signaling Inhibitor Trichodimerol Fungal metabolite Vasculogenic mimicry
This work was supported by a grant from the Stiftung Rheinland-Pfalz für Innovation. We are very thankful to Prof. H. Anke for providing the crude extracts for the screening as well as Trichoderma longibrachiatum strain 049-2000. We thank Prof. S. Dooley, Medical Faculty of Mannheim, for providing the (AGCCAGACA)9MLP-Luc reporter plasmid, Prof. B. Brüne, University of Frankfurt, for providing the HepG2-pH3SVL cells, and Prof. O. Sterner, University of Lund, for the structure elucidation.
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