title: Inhibition of TGF-β signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol.
abstract: 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.
authors.affiliation: Institute of Biotechnology and Drug Research (IBWF e. V.), Erwin-Schrödinger-Str.56, 67663, Kaiserslautern, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Serwe
authors.forename: Kristina
authors.initials: K
authors.lastname: Rudolph
authors.forename: Timm
authors.initials: T
authors.lastname: Anke
authors.forename: Gerhard
authors.initials: G
authors.lastname: Erkel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D016212:Transforming Growth Factor beta; D044004:Xanthones; C512910:isoxanthohumol; D053612:Janus Kinases