Inhibition of TGF-β signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol
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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.
KeywordsIsoxanthohumol TGF-β signaling 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 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.
Conflict of interest
The authors declare that they have no conflict of interest.
- 18.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 Press, Inc, San Diego, pp 315–322Google Scholar
- 27.Ray S, Sherman CT, Lu M, Brasier AR (2002) Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/cAMP response element binding protein-binding protein coactivator recruitment and histone acyltransferase activity. Mol Endocrinol 16:824–836PubMedCrossRefGoogle Scholar
- 29.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
- 63.Harikumar KB, Kunnumakkara AB, Ahn KS, Anand P, Krishnan S, Guha S, Aggarwal BB (2009) Modification of the cysteine residues in IκBα kinase and NF-κB (p65) by xanthohumol leads to suppression of NF-κB-regulated gene products and potentiation of apoptosis in leukemia cells. Blood 113:2003–2013PubMedCrossRefGoogle Scholar