This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pastorino, J. G. Articles by Shulga, N. Search for Related Content PubMed PubMed Citation Articles by Pastorino, J. G. Articles by Shulga, N.

Activation of Glycogen Synthase Kinase 3ß Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: John G. Pastorino, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 272, Jefferson Alumni Hall, Philadelphia, PA 19107. Phone: 215-503-5022; Fax: 215-923-2218; E-mail: John.Pastorino{at}jefferson.edu.

Transformed cells are highly glycolytic and overexpress hexokinase II (HXK II). HXK II is capable of binding to the mitochondria through an interaction with the voltage-dependent anion channel (VDAC), an abundant outer mitochondrial membrane protein. The binding of HXK II to mitochondria has been shown to protect against loss of cell viability. Akt activation inhibits apoptosis partly by promoting the binding of HXK II to the mitochondria, but the mechanism through which Akt accomplishes this has not been characterized. The present report shows that Akt mediates the binding of HXK II to the mitochondria by negatively regulating the activity of glycogen synthase kinase 3ß (GSK3ß). On inhibition of Akt, GSK3ß is activated and phosphorylates VDAC. HXK II is unable to bind VDAC phosphorylated by GSK3ß and dissociates from the mitochondria. Inhibition of Akt potentiates chemotherapy-induced cytotoxicity, an effect that is dependent on GSK3ß activation and its attendant ability to disrupt the binding of HXK II to the mitochondria. Moreover, agents that can force the detachment of HXK II from mitochondria in the absence of Akt inhibition or GSK3ß activation promoted a synergistic increase in cell killing when used in conjunction with chemotherapeutic drugs. Such findings indicate that interference with the binding of HXK II to mitochondria may be a practicable modality by which to potentiate the efficacy of conventional chemotherapeutic agents.

This article has been cited by other articles:

				Z. Wang, A. Havasi, J. Gall, R. Bonegio, Z. Li, H. Mao, J. H. Schwartz, and S. C. Borkan GSK3{beta} Promotes Apoptosis after Renal Ischemic Injury J. Am. Soc. Nephrol., February 1, 2010; 21(2): 284 - 294. [Abstract] [Full Text] [PDF]

				M. A. Omar, L. Wang, and A. S. Clanachan Cardioprotection by GSK-3 inhibition: role of enhanced glycogen synthesis and attenuation of calcium overload Cardiovasc Res, January 31, 2010; (2010): cvp421v2 - cvp421. [Abstract] [Full Text] [PDF]

				S. Bonnet, R. Paulin, G. Sutendra, P. Dromparis, M. Roy, K. O. Watson, J. Nagendran, A. Haromy, J. R.B. Dyck, and E. D. Michelakis Dehydroepiandrosterone Reverses Systemic Vascular Remodeling Through the Inhibition of the Akt/GSK3-{beta}/NFAT Axis Circulation, September 29, 2009; 120(13): 1231 - 1240. [Abstract] [Full Text] [PDF]

				P. T. Bhaskar, V. Nogueira, K. C. Patra, S.-M. Jeon, Y. Park, R. B. Robey, and N. Hay mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3{beta} Inhibition Mol. Cell. Biol., September 15, 2009; 29(18): 5136 - 5147. [Abstract] [Full Text] [PDF]

				P. Dromparis and E. D. Michelakis A redox-metabolic-electrical remodeling in the diseased left and right ventricle: direct clinical implications in heart disease and beyond. Focus on "Role of {gamma}-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts" Am J Physiol Cell Physiol, August 1, 2009; 297(2): C231 - C234. [Full Text] [PDF]

				D. B. Zorov, M. Juhaszova, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Regulation and pharmacology of the mitochondrial permeability transition pore Cardiovasc Res, July 15, 2009; 83(2): 213 - 225. [Abstract] [Full Text] [PDF]

				M. Juhaszova, D. B. Zorov, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Role of Glycogen Synthase Kinase-3{beta} in Cardioprotection Circ. Res., June 5, 2009; 104(11): 1240 - 1252. [Abstract] [Full Text] [PDF]

				E. Gurel, K. M. Smeele, O. Eerbeek, A. Koeman, C. Demirci, M. W. Hollmann, and C. J. Zuurbier Ischemic preconditioning affects hexokinase activity and HKII in different subcellular compartments throughout cardiac ischemia-reperfusion J Appl Physiol, June 1, 2009; 106(6): 1909 - 1916. [Abstract] [Full Text] [PDF]

				Y. Wang, W. Feng, W. Xue, Y. Tan, D. W. Hein, X.-K. Li, and L. Cai Inactivation of GSK-3{beta} by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling Diabetes, June 1, 2009; 58(6): 1391 - 1402. [Abstract] [Full Text] [PDF]

				S. Miyamoto, M. Rubio, and M. A. Sussman Nuclear and mitochondrial signalling Akts in cardiomyocytes Cardiovasc Res, May 1, 2009; 82(2): 272 - 285. [Abstract] [Full Text] [PDF]

				L. Arzoine, N. Zilberberg, R. Ben-Romano, and V. Shoshan-Barmatz Voltage-dependent Anion Channel 1-based Peptides Interact with Hexokinase to Prevent Its Anti-apoptotic Activity J. Biol. Chem., February 6, 2009; 284(6): 3946 - 3955. [Abstract] [Full Text] [PDF]

				A. Gimenez-Cassina, F. Lim, T. Cerrato, G. M. Palomo, and J. Diaz-Nido Mitochondrial Hexokinase II Promotes Neuronal Survival and Acts Downstream of Glycogen Synthase Kinase-3 J. Biol. Chem., January 30, 2009; 284(5): 3001 - 3011. [Abstract] [Full Text] [PDF]

				P. Zhai and J. Sadoshima Overcoming an Energy Crisis?: An Adaptive Role of Glycogen Synthase Kinase-3 Inhibition in Ischemia/Reperfusion Circ. Res., October 24, 2008; 103(9): 910 - 913. [Full Text] [PDF]

				E. D. Michelakis, M. R. Wilkins, and M. Rabinovitch Emerging Concepts and Translational Priorities in Pulmonary Arterial Hypertension Circulation, September 30, 2008; 118(14): 1486 - 1495. [Full Text] [PDF]

				S. Yuan, Y. Fu, X. Wang, H. Shi, Y. Huang, X. Song, L. Li, N. Song, and Y. Luo Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis FASEB J, August 1, 2008; 22(8): 2809 - 2820. [Abstract] [Full Text] [PDF]

				Y. Nishino, I. G. Webb, S. M. Davidson, A. I. Ahmed, J. E. Clark, S. Jacquet, A. M. Shah, T. Miura, D. M. Yellon, M. Avkiran, et al. Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse Circ. Res., August 1, 2008; 103(3): 307 - 314. [Abstract] [Full Text] [PDF]

				S. Abu-Hamad, H. Zaid, A. Israelson, E. Nahon, and V. Shoshan-Barmatz Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1: MAPPING THE SITE OF BINDING J. Biol. Chem., May 9, 2008; 283(19): 13482 - 13490. [Abstract] [Full Text] [PDF]

				S. J. Clarke, I. Khaliulin, M. Das, J. E. Parker, K. J. Heesom, and A. P. Halestrap Inhibition of Mitochondrial Permeability Transition Pore Opening by Ischemic Preconditioning Is Probably Mediated by Reduction of Oxidative Stress Rather Than Mitochondrial Protein Phosphorylation Circ. Res., May 9, 2008; 102(9): 1082 - 1090. [Abstract] [Full Text] [PDF]

				L. Sun, S. Shukair, T. J. Naik, F. Moazed, and H. Ardehali Glucose Phosphorylation and Mitochondrial Binding Are Required for the Protective Effects of Hexokinases I and II Mol. Cell. Biol., February 1, 2008; 28(3): 1007 - 1017. [Abstract] [Full Text] [PDF]

				Z. P. Shaik, E. K. Fifer, and G. Nowak Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury Am J Physiol Renal Physiol, February 1, 2008; 294(2): F423 - F432. [Abstract] [Full Text] [PDF]

				C. J. Zuurbier, P. J. M. Keijzers, A. Koeman, H. B. Van Wezel, and M. W. Hollmann Anesthesia's Effects on Plasma Glucose and Insulin and Cardiac Hexokinase at Similar Hemodynamics and Without Major Surgical Stress in Fed Rats Anesth. Analg., January 1, 2008; 106(1): 135 - 142. [Abstract] [Full Text] [PDF]

				W. Kim, J.-H. Yoon, J.-M. Jeong, G.-J. Cheon, T.-S. Lee, J.-I. Yang, S.-C. Park, and H.-S. Lee Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma Mol. Cancer Ther., September 1, 2007; 6(9): 2554 - 2562. [Abstract] [Full Text] [PDF]

				J. Y. Lee, S. J. Yu, Y. G. Park, J. Kim, and J. Sohn Glycogen Synthase Kinase 3{beta} Phosphorylates p21WAF1/CIP1 for Proteasomal Degradation after UV Irradiation Mol. Cell. Biol., April 15, 2007; 27(8): 3187 - 3198. [Abstract] [Full Text] [PDF]

				A. Patenaude, R. G. Deschesnes, J. L.C. Rousseau, E. Petitclerc, J. Lacroix, M.-F. Cote, and R. C.-Gaudreault New Soft Alkylating Agents with Enhanced Cytotoxicity against Cancer Cells Resistant to Chemotherapeutics and Hypoxia Cancer Res., March 1, 2007; 67(5): 2306 - 2316. [Abstract] [Full Text] [PDF]

				S. Li, Y. Zhou, R. Wang, H. Zhang, Y. Dong, and C. Ip Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates Mol. Cancer Ther., March 1, 2007; 6(3): 1031 - 1038. [Abstract] [Full Text] [PDF]

				L. Huc, X. Tekpli, J. A. Holme, M. Rissel, A. Solhaug, C. Gardyn, G. Le Moigne, M. Gorria, M.-T. Dimanche-Boitrel, and D. Lagadic-Gossmann c-Jun NH2-Terminal Kinase-Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis Cancer Res., February 15, 2007; 67(4): 1696 - 1705. [Abstract] [Full Text] [PDF]

				G. Kroemer, L. Galluzzi, and C. Brenner Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev, January 1, 2007; 87(1): 99 - 163. [Abstract] [Full Text] [PDF]