한빛사논문
- 조회3,290
Abstract
Young Chan Chae1, Valentina Vaira2, 3, 4, M. Cecilia Caino1, Hsin-Yao Tang4, Jae Ho Seo1, Andrew V. Kossenkov5, Luisa Ottobrini4, 6, Cristina Martelli4, Giovanni Lucignani7, 8, Irene Bertolini3, 4, Marco Locatelli9, Kelly G. Bryant1, Jagadish C. Ghosh1, Sofia Lisanti1, Bonsu Ku10, Silvano Bosari3, 4, Lucia R. Languino11, David W. Speicher5, 12, Dario C. Altieri1
Corresponding author : Dario C. Altieri
1 Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
2 Istituto Nazionale Genetica Molecolare “Romeo and Enrica Invernizzi”, Milan 20122, Italy
3 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
4 Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
5 Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA
6 Institute for Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan 20090, Italy
7 Department of Health Sciences, University of Milan, Milan 20142, Italy
8 Department of Diagnostic Services, Unit of Nuclear Medicine, San Paolo Hospital, Milan 20142, Italy
9 Division of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
10 Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea
11 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
12 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
Summary
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.
Keywords : mitochondria; Akt; PDK1; hypoxia; metabolism; tumor cell proliferation
논문정보
- Research article
- 2016년 08월 (BRIC 등록일 2016-08-12)
- 국내+국외 연구진
- 생명과학 > 노화/암생물학
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