A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis

Mol Cancer Res. 2014 Oct;12(10):1520-31. doi: 10.1158/1541-7786.MCR-13-0682. Epub 2014 Aug 7.


Tumor growth, progression, and response to the hypoxic tumor microenvironment involve the action of hypoxia-inducible transcription factors, HIF1 and HIF2. HIF is a heterodimeric transcription factor containing an inducible HIFα subunit and a constitutively expressed HIFβ subunit. The signaling pathways operational in macrophages regulating hypoxia-induced HIFα stabilization remain the subject of intense investigation. Here, it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia-induced HIF1α (HIF1A) and HIF2α (EPAS1) stability in macrophages. Using genetic mouse models and pan-PI3K as well as isoform-specific inhibitors, inhibition of the PI3K/AKT pathway blocked the accumulation of HIFα protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFα via the 26S proteasome. Mechanistically, a macrophage-dominant PI3K isoform (p110γ) directed tumor growth, angiogenesis, metastasis, and the HIFα/VEGF axis. Moreover, a pan-PI3K inhibitor (SF1126) blocked tumor-induced angiogenesis and inhibited VEGF and other proangiogenic factors secreted by macrophages. These data define a novel molecular mechanism by which PTEN/PI3K/AKT regulates the proteasome-dependent stability of HIFα under hypoxic conditions, a signaling pathway in macrophages that controls tumor-induced angiogenesis and metastasis.

Implications: This study indicates that PI3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Hypoxia / drug effects
  • Cell Proliferation / drug effects
  • Chromones / pharmacology
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Isoenzymes / metabolism
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Mice
  • Models, Biological
  • Neoplasm Metastasis
  • Neoplasms / blood supply*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Neovascularization, Pathologic / enzymology*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Oligopeptides / pharmacology
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects
  • Vascular Endothelial Growth Factor A / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Chromones
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoenzymes
  • Oligopeptides
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • SF 1126
  • Vascular Endothelial Growth Factor A
  • endothelial PAS domain-containing protein 1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Proteasome Endopeptidase Complex