Glycine as a potent anti-angiogenic nutrient for tumor growth.
Accumulating lines of evidence suggest a possibility that glycine is useful as an immuno-modulating amino acid. Glycine most likely prevents the lipopolysaccharide (LPS)-induced elevation of intracellular Ca(2+) concentration in Kupffer cells, thereby minimizing LPS receptor signaling and cytokine production. Moreover, it was reported that dietary glycine inhibits the growth of tumors. Vascular endothelial growth factor (VEGF) plays a critical role in cancer progression by promoting new blood vessel formation. Activation of VEGF receptor has been shown to result in activation of phospholipase C-gamma and increases in intracellular Ca(2+) concentration. The VEGF-induced cell proliferation is dependent on intracellular Ca(2+) concentration. The effects of glycine on VEGF-induced increases in intracellular Ca(2+) concentration in endothelial cell line (CPA) were studied. The VEGF increased intracellular Ca(2+) concentration rapidly, but glycine blunted increases in intracellular Ca(2+) concentration due to VEGF. Further, the inhibitory effects of glycine were prevented by low concentrations of strychnine (1 micromol/L) or incubation with chloride-free buffer. Moreover, glycine increased influx of radiolabeled chloride into CPA cells approximately 10-fold. Furthermore, mRNA 92% identical to the beta-subunit of the glycine-gated chloride channel from spinal cord was identified in endothelial cells using reverse transcription-polymerase chain reaction. Finally, glycine significantly diminished serum-stimulated proliferation and migration of endothelial cells. These data indicate that the inhibitory effect of glycine on growth and migration of endothelial cells is due to activation of a glycine-gated chloride channel. This hyperpolarizes the cell membrane and blocks influx of Ca(2+), thereby minimizing growth factor-mediated signaling. Therefore, glycine can be used not only for treatment of inflammation, but also for chemoprevention and treatment of carcinoma.
Yamashina
Shunhei
S
Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
Ikejima
Kenichi
K
Rusyn
Ivan
I
Sato
Nobuhiro
N
D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018118:Chloride Channels / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005998:Glycine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy*; D013331:Strychnine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D018118:Chloride Channels; D042461:Vascular Endothelial Growth Factor A; D013331:Strychnine; D002118:Calcium; D005998:Glycine