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

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Matsumoto Y, Motoki T, Kubota S, Takigawa M, Tsubouchi H, Gohda E

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

Biochem Biophys Res Commun. 2008 Feb 1;366(1):110-6. doi: 10.1016/j.bbrc.2007.11.089. Epub 2007 Nov 29.

PubMed ID

18053801 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Valproic acid	Hepatocyte growth factor	Protein	Humans	Unknown	Inhibitor	Details
Valproic acid	Histone deacetylase (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details