title: The antineoplastic effect of carnosine is accompanied by induction of PDK4 and can be mimicked by L-histidine.
abstract: Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide that shows antineoplastic effects in cell culture as well as in animal experiments. Since its mode of action and the targets at the molecular level have not yet been elucidated, we performed qRT-PCR experiments with RNA isolated from glioblastoma cell lines treated with carnosine, β-alanine, L-alanine, L-histidine and the dipeptide L-alanine-L-histidine. The experiments identified a strong induction of expression of the gene encoding pyruvate dehydrogenase 4 (PDK4) under the influence of carnosine and L-histidine, but not by the other substances employed. In addition, inhibition of cell viability was only detected in cells treated with carnosine and L-histidine, with the latter showing a significantly stronger effect than carnosine. Since the tumor cells expressed the tissue form of carnosinase (CN2) but almost no serum carnosinase (CN1), we conclude that cleavage by CN2 is a prerequisite for the antineoplastic effect of carnosine. In addition, enhanced expression of PDK4 under the influence of carnosine/L-histidine opens a new perspective for the interpretation of the ergogenic potential of dietary β-alanine supplementation and adds a new contribution to a growing body of evidence that single amino acids can regulate key metabolic pathways important in health and disease.
authors.affiliation: Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Leipzig AöR, Liebigstraße 20, 04103, Leipzig, Germany, Ulrike.Letzien@medizin.uni-leipzig.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Letzien
authors.forename: Henry
authors.initials: H
authors.lastname: Oppermann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Meixensberger
authors.forename: Frank
authors.initials: F
authors.lastname: Gaunitz
mesh_terms: D000409:Alanine / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D002336:Carnosine / Q000378:metabolism*; D045744:Cell Line, Tumor; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D006639:Histidine; D019289:Pyruvic Acid; D002336:Carnosine; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D000409:Alanine