title: Ras-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis.
abstract: BACKGROUND
  Even though altered metabolism representing a hallmark of cancer was proposed nearly a century ago, recent technological advances have allowed investigators to continue uncovering a previously unrecognized complexity of metabolic programs that drive tumorigenesis beyond that of aerobic glycolysis.
  
  
  METHODS
  The bioenergetic state of a diverse panel of glioblastoma models, including isogenic lines derived from a genetically engineered adult astrocytic mouse model and patient-derived glioblastoma stem cells, was determined at baseline and in stressed conditions. Mechanisms contributing to the discovered metabolic phenotypes were determined through molecular and chemical perturbation, and their biological consequences were evaluated in vivo and in patient samples.
  
  
  RESULTS
  Attenuated mitochondrial reserve capacity was identified as a common metabolic phenotype in glioblastoma lines. This phenotype was linked mechanistically with the capacity of Ras-mediated signaling to inhibit pyruvate dehydrogenase (PDH) activity through downregulation of PDH phosphatase (PDP) expression. PDP1 repression was validated clinically in patient-derived samples, suggesting that aberrant cellular signaling typical of glioblastoma actively modulates PDH activity. This phenotype was reversed through both chemical and molecular perturbation. Restoration of PDH activity through stable expression of PDP1-impaired tumorigenic potential.
  
  
  CONCLUSIONS
  These findings support the central role that PDH regulation plays as a downstream consequence of aberrant signaling associated with gliomagenesis and the scientific rationale to continue to develop and test clinical strategies designed to activate PDH as a form of anticancer therapy in glioblastoma.
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: Antony
authors.initials: A
authors.lastname: Prabhu
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Sarcar
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: Peter
authors.initials: P
authors.lastname: Forsyth
authors.affiliation: Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.F.); Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (P.C.); Department of Pathology and Laboratory Medicine and Neurology, Lineberger Comprehensive Cancer Center and University of North Carolina, Chapel Hill, North Carolina (C.R.M.); Department of Neurologic Surgery and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio (S-H.K., I.N.).
authors.forename: Prakash
authors.initials: P
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; D018631:ras Proteins
keywords: Ras; glioblastoma; pyruvate dehydrogenase; spare respiratory capacity; tumor metabolism