title: Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells.
abstract: BACKGROUND
  Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells.
  
  
  RESULTS
  BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1α (HIF-1α) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1α and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia.
  
  
  CONCLUSIONS
  Taken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells.
authors: College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors: Jimin
authors: J
authors: Shin
authors: Hyo-Jeong
authors: HJ
authors: Lee
authors: Deok-Beom
authors: DB
authors: Jung
authors: Ji Hoon
authors: JH
authors: Jung
authors: Hyo-Jung
authors: HJ
authors: Lee
authors: Eun-Ok
authors: EO
authors: Lee
authors: Seok Geun
authors: SG
authors: Lee
authors: Beom Sang
authors: BS
authors: Shim
authors: Seung Hoon
authors: SH
authors: Choi
authors: Seong Gyu
authors: SG
authors: Ko
authors: Kwang Seok
authors: KS
authors: Ahn
authors: Soo-Jin
authors: SJ
authors: Jeong
authors: Sung-Hoon
authors: SH
authors: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000094062:Betulinic Acid
chemical_list: D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053978:Pentacyclic Triterpenes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D000094062:Betulinic Acid