Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid
- Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Okayama 700-8530 (Japan)
- Department of Biochemistry and Molecular Dentistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Okayama 700-8525 (Japan)
- Digestive Disease and Life-style Related Disease, Health Research Human and Environmental Sciences, Kagoshima University, Graduate School of Medicine and Dental Sciences, Sakuragaoka, Kagoshima 890-8520 (Japan)
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{sub 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.
- OSTI ID:
- 21043600
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 366, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2007.11.089; PII: S0006-291X(07)02510-7; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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