Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Volume 1787, Issue 5, Pages 553-560Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbabio.2009.03.003
Keywords
Warburg effect; Mitochondria; Hexokinase II; 3-Bromopyruvate; Apoptosis
Categories
Funding
- NCI NIH HHS [R01 CA100428, CA085563, R01 CA109041-05, CA109041, R01 CA085563, R01 CA109041, CA100428, R01 CA085563-07, R01 CA100428-05] Funding Source: Medline
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It has long been observed that cancer cells rely more on glycolysis to generate ATP and actively use certain glycolytic metabolic intermediates for biosynthesis. Hexokinase II (HKII) is a key glycolytic enzyme that plays a role in the regulation of the mitochondria-initiated apoptotic cell death. As a potent inhibitor of hexokinase, 3-bromopyruvate (3-BrPA) is known to inhibit cancer cell energy metabolism and trigger cell death, supposedly through depletion of cellular ATP. The current study showed that 3-BrPA caused a covalent modification of HKII protein and directly triggered its dissociation from mitochondria, leading to a specific release of apoptosis-inducing factor (AIF) from the mitochondria to cytosol and eventual cell death. Co-immunoprecipitation revealed a physical interaction between HKII and AIR Using a competitive peptide of HKII, we showed that the dissociation of hexokinase If from mitochondria alone could cause apoptotic cell death, especially in the mitochondria-deficient rho(0) cells that highly express HKII Interestingly. the dissociation of HKII itself did not directly affect the mitochondrial membrane potential, ROS generation, and oxidative phosphorylation. Our study suggests that the physical association between HKII and AIF is important for the normal localization of AIF in the mitochondria, and disruption of this protein complex by 3-BrPA leads to their release from the mitochondria and eventual cell death. (c) 2009 Elsevier B.V. All rights reserved.
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