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Glycine inhibits angiogenic signaling in human hepatocellular carcinoma cells

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Abstract

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with limited susceptibility to chemotherapy. Modern targeted therapies are aimed at specific properties of this neoplasm. Glycine is a simple non-essential amino acid with potential antiangiogenic effects. In this study, the amino acid’s effect on angiogenic signaling in an in vitro model of HCC was evaluated. HepG2 and Huh7 cells were treated with glycine-free DMEM supplemented with 0, 0.01, 0.1, 1.0, 2.0, 5.0 and 10 mM glycine. The direct effects of glycine on the viability of HCC cells were monitored using MTT assay. To detect angiogenic signaling, mRNA and protein levels of vascular endothelial growth factor (VEGF-A) were measured using RT-PCR and Western Blot assays. To determine whether or not glycine receptors (GlyR) played a significant role, the specific antagonist, strychnine, was used as a direct inhibitor. Western Blotting was performed to show the presence of GlyR. While there was no direct pro- or antiproliferative effect of either glycine or strychnine in both cell lines, glycine was shown to significantly decrease VEGF-A expression on mRNA and protein level up to 63 % in both cell lines. This effect was blunted by the presence of strychnine. GlyR was also identified in both cell lines. Glycine decreases GlyR-dependent, VEGF-A-mediated, angiogenic signaling in human HCC and thus might be a promising additive to chemotherapy treatment strategies for highly vascularized tumors.

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Acknowledgments

The authors would like to thank Nadya Phillips-Houben for language editing.

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Authors and Affiliations

  1. Department of General and Transplant Surgery, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

    Helge Bruns, Marius Petrulionis, Daniel Schultze, Mohammed Al Saeedi, Shibo Lin, Kenya Yamanaka, Marius Ambrazevičius & Peter Schemmer

  2. Center of Abdominal Surgery, Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania

    Marius Petrulionis, Marius Ambrazevičius & Kęstutis Strupas

  3. Department of General and Transplant Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Peter Schemmer

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  1. Helge Bruns
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H. Bruns and M. Petrulionis have contributed equally to this article.

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Bruns, H., Petrulionis, M., Schultze, D. et al. Glycine inhibits angiogenic signaling in human hepatocellular carcinoma cells. Amino Acids 46, 969–976 (2014). https://doi.org/10.1007/s00726-013-1662-2

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