title: Regulation of O2 consumption by the PI3K and mTOR pathways contributes to tumor hypoxia.
abstract: BACKGROUND
  Inhibitors of the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathway are currently in clinical trials. In addition to antiproliferative and proapoptotic effects, these agents also diminish tumor hypoxia. Since hypoxia is a major cause of resistance to radiotherapy, we sought to understand how it is regulated by PI3K/mTOR inhibition.
  
  
  METHODS
  Whole cell, mitochondrial, coupled and uncoupled oxygen consumption were measured in cancer cells after inhibition of PI3K (Class I) and mTOR by pharmacological means or by RNAi. Mitochondrial composition was assessed by immunoblotting. Hypoxia was measured in spheroids, in tumor xenografts and predicted with mathematical modeling.
  
  
  RESULTS
  Inhibition of PI3K and mTOR reduced oxygen consumption by cancer cell lines is predominantly due to reduction of mitochondrial respiration coupled to ATP production. Hypoxia in tumor spheroids was reduced, but returned after removal of the drug. Murine tumors had increased oxygenation even in the absence of average perfusion changes or tumor necrosis.
  
  
  CONCLUSIONS
  Targeting the PI3K/mTOR pathway substantially reduces mitochondrial oxygen consumption thereby reducing tumor hypoxia. These alterations in tumor hypoxia should be considered in the design of clinical trials using PI3K/mTOR inhibitors, particularly in conjunction with radiotherapy.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Kelly
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Kamila
authors.initials: K
authors.lastname: Hussien
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Kannan
authors.affiliation: Department of Mechanical Engineering, University College London, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Shipley
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ashton
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Stratford
authors.affiliation: Mathematical Institute, University of Oxford, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Pearson
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK. Electronic address: ruth.muschel@gmail.com.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D007093:Imidazoles; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: Hypoxia; Oxidative metabolism; PI3K; Reoxygenation; mTOR