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Cancer Cell. 2016 Aug 8;30(2):257-272. doi: 10.1016/j.ccell.2016.07.004.

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming.

Author information

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; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
3
Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
4
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
5
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.
6
Department of Health Sciences, University of Milan, Milan 20142, Italy; Department of Diagnostic Services, Unit of Nuclear Medicine, San Paolo Hospital, Milan 20142, Italy.
7
Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
8
Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
9
Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
10
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
11
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.
12
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.

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.

KEYWORDS:

Akt; PDK1; hypoxia; metabolism; mitochondria; tumor cell proliferation

PMID:
27505672
PMCID:
PMC5131882
DOI:
10.1016/j.ccell.2016.07.004
[Indexed for MEDLINE]
Free PMC Article

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