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The antineoplastic effect of carnosine is accompanied by induction of PDK4 and can be mimicked by l-histidine

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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.

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Acknowledgments

We like to thank Dr. Hans-Heinrich Foerster from the Genolytic GmbH (Leipzig, Germany) for genotyping and confirmation of cell identity. We also thank Berthold Technologies (Bad Wildbad, Germany) for the kind disposal of a Mithras LB 940 Multimode Microplate Reader and last not least Mr. Rainer Baran-Schmidt for technical assistance.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Leipzig AöR, Liebigstraße 20, 04103, Leipzig, Germany

    Ulrike Letzien, Henry Oppermann, Jürgen Meixensberger & Frank Gaunitz

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  1. Ulrike Letzien
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  2. Henry Oppermann
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  3. Jürgen Meixensberger
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  4. Frank Gaunitz
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Corresponding author

Correspondence to Frank Gaunitz.

Additional information

U. Letzien and H. Oppermann contributed equally to the work.

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726_2014_1664_MOESM1_ESM.tif

Fig. 1_to_supplement_2 Viability of HEK293 cells in the presence of carnosine. Human embryonic kidney cells (HEK293) were cultivated in different concentrations of carnosine, and cell viability was determined after 24, 48 and 72 h. Viability was determined by CellTiterGlo (Fig. 1a) and CellTiterBlue assay (Fig. 1b). Experiments were performed in sextuplicate. *: p < 5 × 10−2; **: p < 5*10−3; ***: p < 5x10−4. (TIFF 4692 kb)

726_2014_1664_MOESM2_ESM.tif

PDK4: Cells from the non-cancerous human embryonic kidney cell line HEK293 were incubated in the absence and presence of carnosine and l-histidine for 24 h, and the relative expression of mRNA encoding PDK4 was determined and compared to untreated control. Measurement was performed as quintuplicate. p < 5x10−4; **: p < 5x10−3; *: p < 5x10−2. (TIFF 3839 kb)

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Letzien, U., Oppermann, H., Meixensberger, J. et al. The antineoplastic effect of carnosine is accompanied by induction of PDK4 and can be mimicked by l-histidine. Amino Acids 46, 1009–1019 (2014). https://doi.org/10.1007/s00726-014-1664-8

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  • DOI: https://doi.org/10.1007/s00726-014-1664-8

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