Antitumor activity of methyl gallate by inhibition of focal adhesion formation and Akt phosphorylation in glioma cells

• Published in: Biochimica et biophysica acta 2013-08, Vol.1830 (8), p.4017-4029
• Main Authors: Lee, Sang-Hyun, Kim, Jin Kyu, Kim, Dae Won, Hwang, Hyun Sook, Eum, Won Sik, Park, Jinseu, Han, Kyu Hyung, Oh, Joa Sub, Choi, Soo Young
• Format: Article
• Language: English
• Subjects: Acer; adhesion; Animals; anti-infective properties; antineoplastic agents; Antineoplastic Agents - pharmacology; antioxidants; bark; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; calcium; Calcium - metabolism; Cell Line, Tumor; Cell migration; cell movement; Cell Movement - drug effects; cell proliferation; Cell Survival - drug effects; cell viability; cells; Extracellular Signal-Regulated MAP Kinases - metabolism; fluorescent antibody technique; Focal adhesion; Focal Adhesions - drug effects; Gallic Acid - analogs & derivatives; Gallic Acid - pharmacology; Gallic Acid - therapeutic use; Glioma; Glioma - drug therapy; Glioma - pathology; Glutamate; glutamic acid; humans; Methyl gallate; neoplasm cells; Phosphorylation; protein kinase C; Protein Kinase C - physiology; Proto-Oncogene Proteins c-akt - metabolism; Rats; signal transduction
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.03.030

Methyl gallate (MG) possesses a wide range of biological properties that include anti-oxidant, anti-inflammatory, and anti-microbial activities. However, its anti-tumor activity has not been extensively examined in cancer cells. Thus, we examined the effect of MG in both glutamate-induced rat C6 and human U373 glioma cell proliferation and migration. MG was isolated from the stem bark of Acer barbinerve. Cell viability and migration were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch wound-healing assay, respectively. Focal adhesion formation was detected with immunofluorescence. Treatment of C6 and U373 glioma cells with MG significantly reduced cell viability, migration, and Akt phosphorylation level. Glutamate stimulation markedly increased the level of ERK1/2 phosphorylation. However, cells treated with MG displayed decreased ERK1/2 phosphorylation. Inhibition of ERK1/2 by MG or MEK1/2 inhibitor significantly inhibited paxillin phosphorylation at Ser83 and focal adhesion turn-over produced inefficient glioma cell migration. In addition, activation of Akt and ERK1/2 upon glutamate stimulation was independently regulated by Ca2+ and protein kinase C activity, respectively, via the α-amino-3-hydroxy-5-methy-4-isoxazolepropionate acid glutamate receptor and metabotropic glutamate receptor. Our results clearly indicate that MG has a strong anti-tumor effect through the down-regulation of the Akt and ERK1/2 signaling pathways. Thus, methyl gallate is a potent anti-tumor and novel therapeutic agent for glioma. •Methyl gallate (MG) possesses a wide range of biological properties but the function of MG in glioma cells is still unclear.•MG was isolated from the stem bark of A. barbinerve.•MG significantly reduced cell viability, migration, and Akt and ERK1/2 phosphorylation level.•MG has a strong anti-tumor effect through the down-regulation of the Akt and impairment of the focal adhesion turnover.•MG is a potent anti-tumor and novel therapeutic agent for glioma.