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1.
Oncogene ; 27(34): 4636-43, 2008 Aug 07.
Article in English | MEDLINE | ID: mdl-18408762

ABSTRACT

Cellular bio-energetic metabolism and mitochondria are recognized as potential targets for anticancer agents, due to the numerous relevant peculiarities cancer cells exhibit. Jasmonates are anticancer agents that interact directly with mitochondria. The aim of this study was to identify mitochondrial molecular targets of jasmonates. We report that jasmonates bind to hexokinase and detach it from the mitochondria and its mitochondrial anchor-the voltage-dependent anion channel (VDAC), as judged by hexokinase immunochemical and activity determinations, surface plasmon resonance analysis and planar lipid bilayer VDAC-activity analysis. Furthermore, the susceptibility of cancer cells and mitochondria to jasmonates is dependent on the expression of hexokinase, evaluated using hexokinase-overexpressing transfectants and its mitochondrial association. Many types of cancer cells exhibit overexpression of the key glycolytic enzyme, hexokinase, and its excessive binding to mitochondria. These characteristics are considered to play a pivotal role in cancer cell growth rate and survival. Thus, our findings provide an explanation for the selective effects of jasmonates on cancer cells. Most importantly, this is the first demonstration of a cytotoxic mechanism based on direct interaction between an anticancer agent and hexokinase. The proposed mechanism can serve to guide development of a new selective approach for cancer therapy.


Subject(s)
Acetates/metabolism , Cyclopentanes/metabolism , Hexokinase/metabolism , Mitochondria/metabolism , Oxylipins/metabolism , Acetates/pharmacology , Adenosine Triphosphate/metabolism , Animals , Cell Death/drug effects , Cell Death/genetics , Cyclopentanes/pharmacology , DNA Damage , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Hexokinase/genetics , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C , Mitochondria/drug effects , Mitochondrial Swelling/drug effects , Neoplasms/metabolism , Oxylipins/pharmacology , Protein Binding , Rats , Transfection , Tumor Cells, Cultured , Voltage-Dependent Anion Channels/metabolism
2.
Curr Pharm Des ; 12(18): 2249-70, 2006.
Article in English | MEDLINE | ID: mdl-16787253

ABSTRACT

Research over the last decade has extended the prevailing view of mitochondria to include functions well beyond the critical bioenergetics role in supplying ATP. It is now recognized that mitochondria play a crucial role in cell signaling events, inter-organelle communication, aging, many diseases, cell proliferation and cell death. Apoptotic signal transmission to the mitochondria results in the efflux of a number of potential apoptotic regulators to the cytosol that trigger caspase activation and lead to cell destruction. Accumulating evidence indicates that the voltage-dependent anion channel (VDAC) is involved in this release of proteins via the outer mitochondrial membrane. VDAC in the outer mitochondrial membrane is in a crucial position in the cell, forming the main interface between the mitochondrial and the cellular metabolisms. VDAC has been recognized as a key protein in mitochondria-mediated apoptosis since it is the proposed target for the pro- and anti-apoptotic Bcl2-family of proteins and due to its function in the release of apoptotic proteins located in the inter-membranal space. The diameter of the VDAC pore is only about 2.6-3 nm, which is insufficient for passage of a folded protein like cytochrome c. New work suggests pore formation by homo-oligomers of VDAC or hetero-oligomers composed of VDAC and pro-apoptotic proteins such as Bax or Bak. This review provides insights into the central role of VDAC in cell life and death and emphasizes its function in the regulation of mitochondria-mediated apoptosis and, thereby, its potential as a rational target for new therapeutics.


Subject(s)
Apoptosis , Mitochondria/metabolism , Signal Transduction , Voltage-Dependent Anion Channels/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Arsenic Trioxide , Arsenicals/pharmacology , Arsenicals/therapeutic use , Calcium/metabolism , Cytochromes c/metabolism , Humans , Ion Channel Gating/drug effects , Mitochondria/drug effects , Mitochondrial Membranes/drug effects , Mitochondrial Membranes/metabolism , Models, Molecular , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Oxides/pharmacology , Oxides/therapeutic use , Permeability , Protein Conformation , Protein Folding , Protein Isoforms/chemistry , Protein Isoforms/drug effects , Protein Isoforms/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Ruthenium Red/pharmacology , Signal Transduction/drug effects , Voltage-Dependent Anion Channels/chemistry , Voltage-Dependent Anion Channels/drug effects , bcl-2-Associated X Protein/metabolism
3.
J Membr Biol ; 204(2): 57-66, 2005 Mar.
Article in English | MEDLINE | ID: mdl-16151701

ABSTRACT

In recent years, it has been recognized that there is a metabolic coupling between the cytosol, ER/SR and mitochondria. In this cross-talk, mitochondrial Ca(2+) homeostasis and ATP production and supply play a major role. The primary transporter of adenine nucleotides, Ca(2+)and other metabolites into and out of mitochondria is the voltage-dependent anion channel (VDAC) located at the outer mitochondrial membrane, at a crucial position in the cell. VDAC has been established as a key player in mitochondrial metabolite and ion signaling and it has also been proposed that VDAC is present in extramitochondrial membranes. Thus, regulation of VDAC, as the main interface between mitochondrial and cellular metabolism, by other molecules is of utmost importance. This article reviews localization and function of VDAC, and focuses on VDAC as a skeletal muscle sarcoplasmic reticulum channel. The regulation of VDAC activity by associated proteins and by inhibitors is also presented. Several aspects of the physiological relevance of VDAC to Ca(2+) homeostasis and mitochondria-mediated apoptosis will be discussed.


Subject(s)
Endoplasmic Reticulum/metabolism , Porins/physiology , Sarcoplasmic Reticulum/metabolism , Animals , Apoptosis/physiology , Calcium/metabolism , Intracellular Membranes/physiology , Signal Transduction , Voltage-Dependent Anion Channels
4.
Cell Death Differ ; 12(7): 751-60, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15818409

ABSTRACT

The role of the voltage-dependent anion channel (VDAC) in cell death was investigated using the expression of native and mutated murine VDAC1 in U-937 cells and VDAC inhibitors. Glutamate 72 in VDAC1, shown previously to bind dicyclohexylcarbodiimide (DCCD), which inhibits hexokinase isoform I (HK-I) binding to mitochondria, was mutated to glutamine. Binding of HK-I to mitochondria expressing E72Q-mVDAC1, as compared to native VDAC1, was decreased by approximately 70% and rendered insensitive to DCCD. HK-I and ruthenium red (RuR) reduced the VDAC1 conductance but not that of E72Q-mVDAC1. Overexpression of native or E72Q-mVDAC1 in U-937 cells induced apoptotic cell death (80%). RuR or overexpression of HK-I prevented this apoptosis in cells expressing native but not E72Q-mVDAC1. Thus, a single amino-acid mutation in VDAC prevented HK-I- or RuR-mediated protection against apoptosis, suggesting the direct VDAC regulation of the mitochondria-mediated apoptotic pathway and that the protective effects of RuR and HK-I rely on their binding to VDAC.


Subject(s)
Apoptosis , Porins/metabolism , Amino Acid Substitution/genetics , Animals , Apoptosis/drug effects , Binding Sites , Gene Expression , Hexokinase/genetics , Hexokinase/metabolism , Humans , Ion Channel Gating/drug effects , Mice , Mitochondria/metabolism , Porins/antagonists & inhibitors , Porins/chemistry , Porins/genetics , Rats , Recombinant Proteins/genetics , Ruthenium Red/pharmacology , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , U937 Cells , Voltage-Dependent Anion Channel 1 , Voltage-Dependent Anion Channels
5.
Eur J Nucl Med ; 7(6): 254-9, 1982.
Article in English | MEDLINE | ID: mdl-6980791

ABSTRACT

A standard heart phantom (University of Iowa design), including discrete myocardial walls, a central blood pool, and a 24-cc transmural "cold" defect, was studied with both planar and transverse tomographic imaging. The heart phantom was filled with 201T1 and placed within a cylindrical tank containing water and 201T1 to simulate nonmyocardial background activity from the thorax. The tomographic imaging system used was a commercially available, rotating, large field-of-view gamma camera. Image reconstruction from 64 sampling angles was performed in a nuclear medicine minicomputer system. The percentage activity in the region of the defect (actual activity of 0) contrasted to the normal wall was compared between planar and 1.25-cm transaxial tomographic slices. Defect activity fell to between 65% and 85% of that of the opposing normal wall in planar images, whereas it fell to between 26% and 49% of that of the normal wall in the tomographic images. In most cases, tomographic defect activity was half or less than that in the planar image. The geographic extent of the defect was seen in an appropriate number of tomographic slices; i.e., the geographic 3.2-cm defect length was predominantly seen in three 1.25-cm transverse slices. We conclude that camera-based tomographic systems show promise for improved 201T1 myocardial defect detection and quantitation over conventional planar images.


Subject(s)
Heart/diagnostic imaging , Thallium , Tomography, Emission-Computed/methods , Humans , Models, Structural , Radioisotopes
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