Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid.
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 E(2) 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.
Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Okayama 700-8530, Japan.
Yohsuke
Y
Matsumoto
Takahiro
T
Motoki
Satoshi
S
Kubota
Masaharu
M
Takigawa
Hirohito
H
Tsubouchi
Eiichi
E
Gohda
D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000378:metabolism*; D014635:Valproic Acid / Q000008:administration & dosage*
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D014635:Valproic Acid; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met