title: The mycotoxin beauvericin induces apoptotic cell death in H4IIE hepatoma cells accompanied by an inhibition of NF-κB-activity and modulation of MAP-kinases.
abstract: Beauvericin is a world-spread mycotoxin with a high toxicity in mammalian cells. However, its molecular mechanism of action is not fully understood. Using different cancer cell lines (HepG2, C6, Hct116 and H4IIE), we could show that the cyclic peptide is highly toxic (MTT assay) with IC50 values in low micromolar range. As a molecular mechanism of cell death, necrosis was detected in C6 glioma cells (PI staining), but apoptosis prevails in H4IIE hepatoma cells (caspase 3/7 activity, nuclear fragmentation). In H4IIE cells, beauvericin rapidly decreases the phosphorylation of ERK and strongly increases JNK phosphorylation, while p38 phosphorylation was not affected. Furthermore, a strong inhibition of NF-κB signalling was detectable in H4IIE cells. A screening of 21 protein kinases involved in signal transduction pathways (cell proliferation, survival, angiogenesis and metastasis) showed a selective inhibition of src kinase by beauvericin (IC50=9.8μg/ml). We suggest that beauvericin mediates its toxic effects in H4IIE cells, at least in parts, by a distinct modulation of intracellular signalling molecules.
authors.affiliation: Martin-Luther-Universität Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, Weinbergweg 22, Halle/Saale 06120, Germany; Heinrich-Heine-Universität, Institute of Toxicology, P.O. Box 101007, Düsseldorf 40001, Germany. Electronic address: wim.waetjen@landw.uni-halle.de.
authors.forename: Wim
authors.initials: W
authors.lastname: Wätjen
authors.affiliation: Heinrich-Heine-Universität, Institute of Pharmaceutical Biology and Biotechnology, Universitätsstr 1, Düsseldorf 40225, Germany.
authors.forename: Abdessamab
authors.initials: A
authors.lastname: Debbab
authors.affiliation: Heinrich-Heine-Universität, Institute of Toxicology, P.O. Box 101007, Düsseldorf 40001, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hohlfeld
authors.affiliation: Heinrich-Heine-Universität, Institute of Toxicology, P.O. Box 101007, Düsseldorf 40001, Germany.
authors.forename: Yvonni
authors.initials: Y
authors.lastname: Chovolou
authors.affiliation: Heinrich-Heine-Universität, Institute of Pharmaceutical Biology and Biotechnology, Universitätsstr 1, Düsseldorf 40225, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000302:isolation & purification / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009183:Mycotoxins / Q000302:isolation & purification / Q000633:toxicity*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D009183:Mycotoxins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C004456:beauvericin; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Apoptosis; Cytotoxicity; ERK; JNK; MAPK; Mycotoxin; NF-κB