RRC ID 57805
著者 Kumanishi S, Yamanegi K, Nishiura H, Fujihara Y, Kobayashi K, Nakasho K, Futani H, Yoshiya S.
タイトル Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells.
ジャーナル Int J Oncol
Abstract Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor‑3 (DR3) and decoy receptor‑3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF‑A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re‑expression of tumor suppressor genes in cancer cells, but also exert anti‑angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF‑A interference.
巻・号 55(1)
ページ 167-178
公開日 2019-7-1
DOI 10.3892/ijo.2019.4811
PMID 31180533
MeSH Bone Neoplasms / blood supply Bone Neoplasms / drug therapy* Bone Neoplasms / genetics Bone Neoplasms / metabolism Cell Line Cell Line, Tumor Drug Synergism Endothelial Cells / drug effects Endothelial Cells / metabolism Enzyme Inhibitors / pharmacology Epigenesis, Genetic Humans Hydralazine / pharmacology* Neovascularization, Pathologic / drug therapy Neovascularization, Pathologic / genetics Neovascularization, Pathologic / metabolism Neovascularization, Pathologic / pathology Osteosarcoma / blood supply Osteosarcoma / drug therapy* Osteosarcoma / genetics Osteosarcoma / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Receptors, Tumor Necrosis Factor, Member 25 / biosynthesis Receptors, Tumor Necrosis Factor, Member 25 / genetics Transcription, Genetic / drug effects Tumor Necrosis Factor Ligand Superfamily Member 15 / biosynthesis* Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics Valproic Acid / pharmacology* Vascular Endothelial Growth Factor A / metabolism*
IF 3.899
引用数 0
リソース情報
ヒト・動物細胞 Saos-2