The fungal secondary metabolite trichodimerol inhibits TGF-β dependent cellular effects and tube formation of MDA-MB-231 cells.
The transforming growth factor-beta (TGF-beta) family of ligands has a pivotal role as regulators of cell growth, differentiation and migration. Overexpression of TGF-beta has been associated with breast, colon, hepatocellular, lung and pancreatic cancer. Importantly, overexpression of TGF-beta correlates with tumor progression, metastasis, angiogenesis and poor prognostic outcome. Therefore, TGF-beta signaling has emerged as an attractive target for the development of new cancer therapeutics. In a search for metabolites from fungi inhibiting the TGF-beta dependent expression of a reporter gene in HepG2 cells, we found that trichodimerol, a previously isolated bisorbicillinoid, inhibited serine phosphorylation of the TGF-beta activated Smad2/3 transcription factors and antagonized the cellular effects of TGF-beta including reporter gene activation and expression of TGF-beta inducible genes in HepG2 and MDA-MB-231 cells. In addition, trichodimerol blocked IFN-gamma, 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 muM trichodimerol completely abrogated the capillary-like tube formation of MDA-MB-231 cells on Matrigel.
Serwe
Annegret
A
Institute for Biotechnology and Drug Research (IBWF e. V.), Erwin-Schrödinger-Str. 56, 67663, Kaiserslautern, Germany.
Anke
Timm
T
Erkel
Gerhard
G
D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014242:Trichoderma / Q000737:chemistry*
D001952:Bridged-Ring Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D016212:Transforming Growth Factor beta; C099299:trichodimerol; D053612:Janus Kinases