Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways

FASEB J. 2005 Mar;19(3):342-53. doi: 10.1096/fj.04-2175com.

Abstract

Apigenin is a nontoxic dietary flavonoid that has been shown to possess anti-tumor properties and therefore poses special interest for the development of a novel chemopreventive and/or chemotherapeutic agent for cancer. Ovarian cancer is one of the most common causes of cancer death among women. Here we demonstrate that apigenin inhibits expression of vascular endothelial growth factor (VEGF) in human ovarian cancer cells. VEGF plays an important role in tumor angiogenesis and growth. We found that apigenin inhibited VEGF expression at the transcriptional level through expression of hypoxia-inducible factor 1alpha (HIF-1alpha). Apigenin inhibited expression of HIF-1alpha and VEGF via the PI3K/AKT/p70S6K1 and HDM2/p53 pathways. Apigenin inhibited tube formation in vitro by endothelial cells. These findings reveal a novel role of apigenin in inhibiting HIF-1 and VEGF expression that is important for tumor angiogenesis and growth, identifying new signaling molecules that mediate this regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apigenin / pharmacology*
  • Cell Line, Tumor
  • Endothelial Cells / drug effects
  • Enzyme Activation / drug effects
  • Female
  • Gene Expression / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neovascularization, Physiologic / drug effects
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Ovarian Neoplasms
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-mdm2
  • RNA, Messenger / analysis
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Vascular Endothelial Growth Factor A
  • Apigenin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa