title: Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming.
abstract: Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Young Chan
authors: YC
authors: Chae
authors: Istituto Nazionale Genetica Molecolare "Romeo and Enrica Invernizzi", Milan 20122, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors: Valentina
authors: V
authors: Vaira
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: M Cecilia
authors: MC
authors: Caino
authors: Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors: Hsin-Yao
authors: HY
authors: Tang
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Jae Ho
authors: JH
authors: Seo
authors: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
authors: Andrew V
authors: AV
authors: Kossenkov
authors: Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy; Institute for Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan 20090, Italy.
authors: Luisa
authors: L
authors: Ottobrini
authors: Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors: Cristina
authors: C
authors: Martelli
authors: Department of Health Sciences, University of Milan, Milan 20142, Italy; Department of Diagnostic Services, Unit of Nuclear Medicine, San Paolo Hospital, Milan 20142, Italy.
authors: Giovanni
authors: G
authors: Lucignani
authors: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors: Irene
authors: I
authors: Bertolini
authors: Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors: Marco
authors: M
authors: Locatelli
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Kelly G
authors: KG
authors: Bryant
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Jagadish C
authors: JC
authors: Ghosh
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Sofia
authors: S
authors: Lisanti
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors: Bonsu
authors: B
authors: Ku
authors: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
authors: Silvano
authors: S
authors: Bosari
authors: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Lucia R
authors: LR
authors: Languino
authors: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors: David W
authors: DW
authors: Speicher
authors: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: daltieri@wistar.org.
authors: Dario C
authors: DC
authors: Altieri
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D065150:Cellular Reprogramming / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction
chemical_list: C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; PDK1; hypoxia; metabolism; mitochondria; tumor cell proliferation