Abstract
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.
©2014 American Association for Cancer Research.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Cell Hypoxia / drug effects
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Cell Proliferation / drug effects
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Chromones / pharmacology
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Gene Deletion
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Gene Expression Regulation, Neoplastic / drug effects
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Isoenzymes / metabolism
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Macrophages / drug effects
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Macrophages / enzymology*
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Mice
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Models, Biological
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Neoplasm Metastasis
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Neoplasms / blood supply*
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Neoplasms / enzymology
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Neoplasms / genetics
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Neoplasms / pathology*
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Neovascularization, Pathologic / enzymology*
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / pathology
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Oligopeptides / pharmacology
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Proteasome Endopeptidase Complex / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Stability / drug effects
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction / drug effects
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Transcription, Genetic / drug effects
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Chromones
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Hypoxia-Inducible Factor 1, alpha Subunit
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Isoenzymes
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Oligopeptides
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Protein Kinase Inhibitors
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RNA, Messenger
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SF 1126
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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Proteasome Endopeptidase Complex