The fungal secondary metabolite trichodimerol inhibits TGF-β dependent cellular effects and tube formation of MDA-MB-231 cells
- 237 Downloads
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.
- 14.Warr GA, Veitch JA, Walsh AW, Hesler GA, Pirnik DM, Leet JE, Lin PF, Medina IA, McBrien KD, Forenza S, Clark JM, Lam KS (1996) BMS-182123, a fungal metabolite that inhibits the production of TNF-alpha by macrophages and monocytes. J Antibiot (Tokyo) 49:234–240Google Scholar
- 15.White TJ, Bruns T, Lee S, Taylor AW (1990) Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ (eds) PCR protocols: a guide to methods and applications. Academic, San Diego, pp 315–322Google Scholar
- 16.Erkel G, Belahmer H, Serwe A, Anke T, Kunz H, Kolshorn H, Liermann J, Opatz T (2008) Oxacyclododecindione, a novel inhibitor of IL-4 signaling from Exserohilum rostratum. J Antibiot (Tokyo) 61:285–290Google Scholar
- 21.Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA (2002) Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 62:3729–3735PubMedGoogle Scholar
- 26.Souchelnytskyi S, Tamaki K, Engstrom U, Wernstedt C, ten Dijke P, Heldin CH (1997) Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem 272:28107–28115 doi: 10.1074/jbc.272.44.28107 CrossRefPubMedGoogle Scholar
- 27.Liu X, Sun Y, Constantinescu SN, Karam E, Weinberg RA, Lodish HF (1997) Transforming growth factor beta-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc Natl Acad Sci USA 94:10669–10674 doi: 10.1073/pnas.94.20.10669 CrossRefPubMedGoogle Scholar
- 31.Nam J-S, Terabe M, Mamura M, Kang M-J, Chae H, Stuelten C, Kohn E, Tang B, Sabzevari H, Anver MR, Lawrence S, Danielpour D, Lonning S, Berzofsky JA, Wakefield LM (2008) An anti-transforming growth factor β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res 68:3835–3643 doi: 10.1158/0008-5472.CAN-08-0215 CrossRefPubMedGoogle Scholar
- 47.Lee D, Lee JH, Cai XF, Shin JC, Lee K, Hong Y-S, Lee JJ (2005) Fungal metabolites, sorbicillinoid polyketides and their effects on the activation of peroxisome proliferator-activated receptor γ. J Antibiot (Tokyo) 58:615–620Google Scholar