title: Rhapontigenin inhibited hypoxia inducible factor 1 alpha accumulation and angiogenesis in hypoxic PC-3 prostate cancer cells.
abstract: Hypoxia inducible factor 1 alpha (HIF-1α) is frequently over-expressed in the numerous types of cancer and plays an important role in angiogenesis. In the present study, the inhibitory mechanism of rhapontigenin isolated from Vitis coignetiae was investigated on HIF-1α stability and angiogenesis in human prostate cancer PC-3 cells. Rhapontigenin significantly suppressed HIF-1α accumulation at protein level but not at mRNA level in PC-3 cells under hypoxia. Also, rhapontigenin suppressed hypoxia-induced HIF-1α activation in various cancer cells, such as colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF-7), fibrosarcoma (HT-1080) and prostate carcinoma (LNCaP). Interestingly, rhapontigenin had more potency in inhibition of hypoxia-induced HIF-1α expression than that of resveratrol, a known HIF-1α inhibitor. In addition, rhapontigenin promoted hypoxia-induced HIF-1α degradation and cycloheximide (CHX) blocked protein synthesis. A prolyl hydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) is usually utilized to examine whether prolyl hydroxylation is involved in inhibition of HIF-1α accumulation. Here, DMOG recovered HIF-1α accumulation inhibited by rhapontigenin. Immunoprecipitation assay also revealed that rhapotigenin enhanced the binding of hydroxylated HIF-1α to von Hippel-Lindau (VHL) tumor suppressor protein. Furthermore, rhapontigenin reduced vascular endothelial growth factor (VEGF) secretion in hypoxic PC-3 cells as well as suppressed tube formation in human umbilical vein endothelial cells (HUVECs) treated by the conditioned media of hypoxic PC-3 cells. However, anti-angiogenic effect of rhapontigenin in hypoxic PC-3 cells was reversed by DMOG. Taken together, these findings suggest that rhapontigenin inhibits HIF-1α accumulation and angiogenesis in PC-3 prostate cancer cells.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Deok-Beom
authors.initials: DB
authors.lastname: Jung
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Lee
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Kyoo Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013267:Stilbenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013267:Stilbenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C431126:rhapontigenin; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C040947:oxalylglycine