title: Pomolic acid suppresses HIF1α/VEGF-mediated angiogenesis by targeting p38-MAPK and mTOR signaling cascades.
abstract: BACKGROUND
  Pomolic acid (PA), an active triterpenoid from Euscaphis japonica, inhibits the proliferation of a variety of cancer cells, but the molecular mechanisms of the anti-angiogenic potential of PA have not been fully elucidated in breast cancer cells.
  
  
  OBJECTIVE
  We investigated the molecular mechanisms underlying the anti-angiogenic effect of PA in epidermal growth factor (EGF)-responsive human breast cancer cells, MCF-7 and MDA-MB-231, and human umbilical vascular endothelial cells (HUVEC).
  
  
  METHODS
  Effects of PA on EGF-induced HIF1α/VEGF expression in MCF-7, MDA-MB-231 and HUVEC were assayed. As to the mechanisms, EGF-mediated MAPKs, PI3K/Akt, and mTOR signaling pathway were performed. Wound healing and invasion assay, tube formation assay, immunoblot assay, real-time PCR, luciferase gene assay, electrophoretic mobility shift assay and immunofluorescence staining were used for assessment.
  
  
  RESULTS
  PA significantly and selectively suppressed EGF-induced HIF1α/VEGF expression, whereas it did not affect the expression of HIF1β in MCF-7 and MDA-MB-231. Furthermore, PA inhibited EGF-induced angiogenesis in vitro and downregulated HIF1α/VEGF expression in HUVEC. Mechanistically, we found that the inhibitory effects of PA on HIF1α/VEGF expression are associated with inhibition of HIF1α/VEGF expression through an EGF-dependent mechanism. In addition, PA suppressed the EGF-induced phosphorylation of p38-MAPK and mTOR.
  
  
  CONCLUSIONS
  PA suppresses EGF-induced HIF1α protein translation by inhibiting the p38-MAPK and mTOR kinase signaling pathways and plays a novel anti-angiogenic role.
authors.affiliation: College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Republic of Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Republic of Korea. Electronic address: jwyoon@kmu.ac.kr.
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Republic of Korea. Electronic address: bdpark@kmu.ac.kr.
authors.forename: Byoungduck
authors.initials: B
authors.lastname: Park
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D061986:MCF-7 Cells; D019684:Magnoliopsida / Q000737:chemistry; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009828:Oleanolic Acid; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; C115535:pomolic acid; C546842:MTOR protein, human
keywords: Angiogenesis; EGF; HIF1α; Pomolic acid; VEGF; mTOR