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Inhibition of TGF-β signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol

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Summary

TGF-β is a multifunctional cytokine that regulates cell proliferation, differentiation, apoptosis and extracellular matrix production. Deregulation of TGF-β production or signaling has been associated with a variety of pathological processes such as cancer, metastasis, angiogenesis and fibrosis. Therefore, TGF-β signaling has emerged as an attractive target for the development of new cancer therapeutics. In a screening program of natural compounds from fungi inhibiting the TGF-β dependent expression of a reporter gene in HepG2 cells, we found that the flavone isoxanthohumol inhibited the binding of the activated Smad2/3 transcription factors to the DNA and antagonized the cellular effects of TGF-β including reporter gene activation and expression of TGF-β induced genes in HepG2 and MDA-MB-231 cells. In an in vitro angiogenesis assay, isoxanthohumol (56 μM) strongly decreased the formation of capillary-like tubules of MDA-MB-231 cells on Matrigel. In addition, we found that isoxanthohumol blocked IFN-γ, IL-4 and IL-6 dependent Jak/Stat signaling and strongly inhibited the induction of pro-inflammatory genes in MonoMac6 cells at the transcriptional level after LPS/TPA treatment.

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Acknowledgements

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 harzianum IBWF278b-95. 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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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Biotechnology and Drug Research (IBWF e. V.), Erwin-Schrödinger-Str.56, 67663, Kaiserslautern, Germany

    Annegret Serwe & Kristina Rudolph

  2. Department of Biotechnology, University of Kaiserslautern, Paul-Ehrlich-Str. 23, 67663, Kaiserslautern, Germany

    Timm Anke & Gerhard Erkel

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  1. Annegret Serwe
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Correspondence to Gerhard Erkel.

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Serwe, A., Rudolph, K., Anke, T. et al. Inhibition of TGF-β signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol. Invest New Drugs 30, 898–915 (2012). https://doi.org/10.1007/s10637-011-9643-3

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