A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

• Published in: Molecular cancer research Vol. 12; no. 10; pp. 1520 - 1531
• Main Authors: Joshi, Shweta, Singh, Alok R., Zulcic, Muamera, Durden, Donald L.
• Format: Journal Article
• Language: English
• Published: United States 01.10.2014
• Subjects: 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; 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; PTEN Phosphohydrolase - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Transcription, Genetic - drug effects; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1541-7786; 1557-3125; 1557-3125
• DOI: 10.1158/1541-7786.MCR-13-0682

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. Mol Cancer Res; 12(10); 1520–31. ©2014 AACR.