American Association for Cancer Research
00085472can153079-sup-157714_2_supp_0_j8gz20.doc (71 kB)

Suplemental methods from PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

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posted on 2023-03-31, 00:04 authored by Sameer Agnihotri, Brian Golbourn, Xi Huang, Marc Remke, Susan Younger, Rob A. Cairns, Alan Chalil, Christian A. Smith, Stacey-Lynn Krumholtz, Danielle Mackenzie, Patricia Rakopoulos, Vijay Ramaswamy, Michael S. Taccone, Paul S. Mischel, Gregory N. Fuller, Cynthia Hawkins, William L. Stanford, Michael D. Taylor, Gelareh Zadeh, James T. Rutka

Suplemental methods for experiments appearing in supplemental data and expanded details from methods in main manuscript.


Canadian Institutes of Health Research

Brainchild, and the Laurie Berman and Wiley Family Funds for Brain Tumor Research



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.

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