title: A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis.
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.
  
  
  CONCLUSIONS
  This study indicates that PI3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression.
authors.affiliation: UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
authors.forename: Shweta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
authors.forename: Alok R
authors.initials: AR
authors.lastname: Singh
authors.affiliation: UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
authors.forename: Muamera
authors.initials: M
authors.lastname: Zulcic
authors.affiliation: UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California. Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, San Diego, California. SignalRx Pharmaceuticals, San Diego, California. ddurden@ucsd.edu.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002867:Chromones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D009842:Oligopeptides; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C526549:SF 1126