Regulation of hexokinase binding to VDAC |
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Authors: | John G Pastorino Jan B Hoek |
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Institution: | (1) Department of Molecular Biology, University of Medicine and Dentistry of New Jersey, Science Center, Room 316, 2 Medical Center Drive, Stratford, NJ 08084, USA;(2) Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA |
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Abstract: | Hexokinase isoforms I and II bind to mitochondrial outer membranes in large part by interacting with the outer membrane voltage-dependent
anion channel (VDAC). This interaction results in a shift in the susceptibility of mitochondria to pro-apoptotic signals that
are mediated through Bcl2-family proteins. The upregulation of hexokinase II expression in tumor cells is thought to provide
both a metabolic benefit and an apoptosis suppressive capacity that gives the cell a growth advantage and increases its resistance
to chemotherapy. However, the mechanisms responsible for the anti-apoptotic effect of hexokinase binding and its regulation
remain poorly understood. We hypothesize that hexokinase competes with Bcl2 family proteins for binding to VDAC to influence
the balance of pro-and anti-apoptotic proteins that control outer membrane permeabilization. Hexokinase binding to VDAC is
regulated by protein kinases, notably glycogen synthase kinase (GSK)-3β and protein kinase C (PKC)-ɛ. In addition, there is
evidence that the cholesterol content of the mitochondrial membranes may contribute to the regulation of hexokinase binding.
At the same time, VDAC associated proteins are critically involved in the regulation of cholesterol uptake. A better characterization
of these regulatory processes is required to elucidate the role of hexokinases in normal tissue function and to apply these
insights for optimizing cancer treatment. |
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