sf-1126 and Neoplasm-Metastasis

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

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