PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma.
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.
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Sameer
S
Agnihotri
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Brian
B
Golbourn
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, California. Department of Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, California. Department of Biochemistry, Howard Hughes Medical Institute, University of California, San Francisco, California.
Xi
X
Huang
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Marc
M
Remke
Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, California. Department of Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, California. Department of Biochemistry, Howard Hughes Medical Institute, University of California, San Francisco, California.
Susan
S
Younger
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Rob A
RA
Cairns
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Alan
A
Chalil
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Christian A
CA
Smith
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Stacey-Lynn
SL
Krumholtz
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Danielle
D
Mackenzie
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Patricia
P
Rakopoulos
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Vijay
V
Ramaswamy
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Michael S
MS
Taccone
Ludwig Institute for Cancer Research, University of California, San Diego, California.
Paul S
PS
Mischel
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Gregory N
GN
Fuller
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. Department of Pathology, Hospital for Sick Children, Ontario, Canada.
Cynthia
C
Hawkins
Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research, Ontario, Canada.
William L
WL
Stanford
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Michael D
MD
Taylor
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. Department of Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, California. Department of Neurosurgery, Toronto Western Hospital, Ontario, Canada. Gelareh Zadeh, University Health Network, Toronto, Ontario, Canada.
Gelareh
G
Zadeh
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. RS McLaughlin, Professor and Chairman, University of Toronto, Toronto, Ontario, Canada. Department of Surgery, Hospital for Sick Children, Ontario, Canada. james.rutka@sickkids.ca.
James T
JT
Rutka
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D049109:Cell Proliferation; D004330:Drosophila; D005909:Glioblastoma / Q000473:pathology*; D006019:Glycolysis / Q000502:physiology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018384:Oxidative Stress / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D017382:Reactive Oxygen Species; D000099202:PTEN-Induced Putative Kinase