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http://purl.uniprot.org/citations/25103499http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25103499http://www.w3.org/2000/01/rdf-schema#comment"

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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."xsd:string
http://purl.uniprot.org/citations/25103499http://purl.org/dc/terms/identifier"doi:10.1158/1541-7786.mcr-13-0682"xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/author"Singh A.R."xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/author"Joshi S."xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/author"Durden D.L."xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/author"Zulcic M."xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/name"Mol Cancer Res"xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/pages"1520-1531"xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/title"A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1alpha and HIF2alpha stability and tumor growth, angiogenesis, and metastasis."xsd:string
http://purl.uniprot.org/citations/25103499http://purl.uniprot.org/core/volume"12"xsd:string
http://purl.uniprot.org/citations/25103499http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/25103499
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