Inhibition of tumor–stromal interaction through HGF/Met signaling by valproic acid

• Published in: Biochemical and biophysical research communications 2008-02, Vol.366 (1), p.110-116
• Main Authors: Matsumoto, Yohsuke, Motoki, Takahiro, Kubota, Satoshi, Takigawa, Masaharu, Tsubouchi, Hirohito, Gohda, Eiichi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ACETATES; APOPTOSIS; BUTYRIC ACID; Carcinoma, Hepatocellular - metabolism; Cell Communication - drug effects; Cell Line; CELL PROLIFERATION; Dermal fibroblast; Dose-Response Relationship, Drug; FIBROBLASTS; Fibroblasts - drug effects; Fibroblasts - metabolism; GENE REGULATION; GROWTH FACTORS; Hepatocyte growth factor; Hepatocyte Growth Factor - metabolism; HEPATOMAS; Histone deacetylase inhibitor; Humans; Induction; INHIBITION; PHOSPHORYLATION; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-met; Receptors, Growth Factor - metabolism; Signal Transduction - drug effects; Stromal Cells - metabolism; Trichostatin A; TUMOR CELLS; Tumor invasion; Valproic acid; Valproic Acid - administration & dosage
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.11.089

Hepatocyte growth factor (HGF), which is produced by surrounding stromal cells, including fibroblasts and endothelial cells, has been shown to be a significant factor responsible for cancer cell invasion mediated by tumor–stromal interactions. We found in this study that the anti-tumor agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, strongly inhibited tumor–stromal interaction. VPA inhibited HGF production in fibroblasts induced by epidermal growth factor (EGF), platelet-derived growth factor, basic fibroblast growth factor, phorbol 12-myristate 13-acetate (PMA) and prostaglandin E2 without any appreciable cytotoxic effect. Other HDAC inhibitors, including butyric acid and trichostatin A (TSA), showed similar inhibitory effects on HGF production stimulated by various inducers. Up-regulations of HGF gene expression induced by PMA and EGF were also suppressed by VPA and TSA. Furthermore, VPA significantly inhibited HGF-induced invasion of HepG2 hepatocellular carcinoma cells. VPA, however, did not affect the increases in phosphorylation of MAPK and Akt in HGF-treated HepG2 cells. These results demonstrated that VPA inhibited two critical processes of tumor–stromal interaction, induction of fibroblastic HGF production and HGF-induced invasion of HepG2 cells, and suggest that those activities serve for other anti-tumor mechanisms of VPA besides causing proliferation arrest, differentiation, and/or apoptosis of tumor cells.