PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma
Autor: | Michael D. Taylor, Gelareh Zadeh, Rob A. Cairns, Vijay Ramaswamy, Marc Remke, Christian A. Smith, Gregory N. Fuller, Michael S. Taccone, Alan Chalil, James T. Rutka, Stacey Krumholtz, William L. Stanford, Brian Golbourn, Xi Huang, Danielle Mackenzie, Cynthia Hawkins, Susan Younger, Sameer Agnihotri, Paul S. Mischel, Patricia Rakopoulos |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Blotting Western Regulator PINK1 Mice SCID Biology Mice 03 medical and health sciences Mice Inbred NOD Animals Humans Glycolysis Cell Proliferation Brain Neoplasms Kinase Immunohistochemistry Warburg effect Oxidative Stress 030104 developmental biology Oncology Anaerobic glycolysis Astrocytes Cancer cell Cancer research Heterografts Drosophila Glioblastoma Reactive Oxygen Species Protein Kinases Pyruvate kinase |
Zdroj: | Cancer Research. 76:4708-4719 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. Cancer Res; 76(16); 4708–19. ©2016 AACR. |
Databáze: | OpenAIRE |
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