title: PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma.
abstract: Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2α mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy.
authors.affiliation: Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Mohlin
authors.affiliation: Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden.
authors.forename: Arash
authors.initials: A
authors.lastname: Hamidian
authors.affiliation: Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: von Stedingk
authors.affiliation: Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Bridges
authors.affiliation: Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wigerup
authors.affiliation: Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bexell
authors.affiliation: Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden. sven.pahlman@med.lu.se.
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D017527:Receptor, IGF Type 2 / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D017527:Receptor, IGF Type 2; D011972:Receptor, Insulin; D017451:Receptors, Somatomedin; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C000597236:IGF1R protein, human; C463659:RPTOR protein, human; C435941:INSR protein, human; C494918:AKT1 protein, human