Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M cells

Salida Mirzoeva, Deuk Kim Nam, Karen Chiu, Carrie A. Franzen, Raymond C. Bergan, Jill C. Pelling

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Progression of cancer leads to hypoxic solid tumors that mount specific cell signaling responses to low oxygen conditions. An important objective of anti-cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. Apigenin is a natural flavone that has been shown to have chemopreventive and/or anticancer properties against a number of tumor types. However, the mechanisms underlying apigenin's chemopreventive properties are not yet completely understood. In this study, we have investigated the effects of apigenin on expression of hypoxia-inducible factor-1 (HIF-1) in human metastatic prostate PC3-M cancer cells. We found that hypoxia induced a time-dependent increase in the level of HIF-1α subunit protein in PC3-M cells, and treatment with apigenin markedly decreased HIF-1α expression under both normoxic and hypoxic conditions. Further, apigenin prevented the activation of the HIF-1 downstream target gene vascular endothelial growth factor (VEGF). We then showed that apigenin inhibited expression of HIF-1α by reducing stability of the protein as well as by reducing the level of HIF-1α mRNA. We also found that apigenin inhibited Akt and GSK-3β phosphorylation in PC3-M cells. Further experiments demonstrated that constitutively active Akt blunted the effect of apigenin on HIF-1α expression. Taken together, our results identify apigenin as a bioflavonoid that inhibits hypoxia-activated pathways linked to cancer progression in human prostate cancer, in particular the PI3K/Akt/GSK-3 pathway. Further studies on the mechanism of action of apigenin will likely provide new insight into its applicability for pharmacologic targeting of HIF-1α for cancer therapeutic or chemopreventive purposes.

Original languageEnglish (US)
Pages (from-to)686-700
Number of pages15
JournalMolecular Carcinogenesis
Volume47
Issue number9
DOIs
StatePublished - Sep 1 2008

Keywords

  • Akt
  • Apigenin
  • Hypoxia
  • Hypoxia-inducible factor-1α
  • Prostate

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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