The fungal secondary metabolite trichodimerol inhibits TGF-β dependent cellular effects and tube formation of MDA-MB-231 cells

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.