Characterization of porin isoforms expressed in tumor cells

Shinohara, Yasuo; Ishida, Toshiki; Hino, Masayuki; Yamazaki, Naoshi; Baba, Yoshinobu; Terada, Hiroshi

doi:10.1046/j.1432-1327.2000.01687.x

Cited by 80 publications

(61 citation statements)

References 31 publications

(47 reference statements)

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“…Alternatively, VDAC1 may represent the predominant form expressed in the tissues tested (41). On the other hand, both VDAC1 and VDAC2 are ubiquitously expressed, while VDAC3 has a more restricted organ distribution (42)(43)(44). VDAC isoforms appear to display different physiological functions (45), each isoform exhibiting different permeability properties (46), and binding of hexokinase, a protein that has also been proposed to be associated to the PTP (47, 48), appears to be a specific feature of VDAC1 (28).…”

Section: Discussionmentioning

confidence: 99%

The Voltage-dependent Anion Channel Is the Target for a New Class of Inhibitors of the Mitochondrial Permeability Transition Pore

Cesura¹,

Pinard²,

Schubenel³

et al. 2003

Journal of Biological Chemistry

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The relevance of the mitochondrial permeability transition pore (PTP) in Ca 2؉ homeostasis and cell death has gained wide attention. Yet, despite detailed functional characterization, the structure of this channel remains elusive. Here we report on a new class of inhibitors of the PTP and on the identification of their molecular target. The most potent among the compounds prepared, Ro 68-3400, inhibited PTP with a potency comparable to that of cyclosporin A. Since Ro 68-3400 has a reactive moiety capable of covalent modification of proteins, [3 H]Ro 68-3400 was used as an affinity label for the identification of its protein target. In intact mitochondria isolated from rodent brain and liver and in SH-SY5Y human neuroblastoma cells, [ 3 H]Ro 68-3400 predominantly labeled a protein of ϳ32 kDa. This protein was identified as the isoform 1 of the voltage-dependent anion channel (VDAC). Both functional and affinity labeling experiments indicated that VDAC might correspond to the site for the PTP inhibitor ubiquinone 0 , whereas other known PTP modulators acted at distinct sites. While Ro 68-3400 represents a new useful tool for the study of the structure and function of VDAC and the PTP, the results obtained provide direct evidence that VDAC1 is a component of this mitochondrial pore.

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Section: Discussionmentioning

confidence: 99%

The Voltage-dependent Anion Channel Is the Target for a New Class of Inhibitors of the Mitochondrial Permeability Transition Pore

Cesura¹,

Pinard²,

Schubenel³

et al. 2003

Journal of Biological Chemistry

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show abstract

“…Enhanced expression of VDAC on tumor mitochondria in comparison to normal tissue has also been observed (Shinohara et al, 2000). Although several isoforms of VDAC are known, they do have similar kinetic characteristics, which indicate that the contribution of VDAC to enhanced HK binding and glucose phosphorylation is due to quantitative differences in binding site availability (Shinohara et al, 2000).…”

Section: The Voltage-dependent Anion Channelmentioning

confidence: 99%

“…Although several isoforms of VDAC are known, they do have similar kinetic characteristics, which indicate that the contribution of VDAC to enhanced HK binding and glucose phosphorylation is due to quantitative differences in binding site availability (Shinohara et al, 2000). The predominant form of VDAC expressed on mitochondria and known to interact with HK is VDAC-1.…”

Section: The Voltage-dependent Anion Channelmentioning

confidence: 99%

Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

2006

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“…The molecular mechanism of HK-mediated protection against cell death involves HK-I and HK-II binding to the outer mitochondrial membrane protein, the voltage-dependent anion channel (VDAC) (8,9,(13)(14)(15)(16). Indeed, VDAC was shown to be up-regulated in cancer cells exhibiting elevated binding to HK-I and/or HK-II (17). Also, it has been recently shown that acute viruses, such as HEV, can protect infected cells from apoptotic death via enhanced VDAC and HK expression (18).…”

mentioning

confidence: 99%

Voltage-dependent Anion Channel 1-based Peptides Interact with Hexokinase to Prevent Its Anti-apoptotic Activity

Arzoine

Zilberberg

Ben-Romano

et al. 2009

Journal of Biological Chemistry

149

226

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In brain and tumor cells, the hexokinase isoforms, HK-I and HK-II, bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. The VDAC domains interacting with these anti-apoptotic proteins were recently defined using site-directed mutagenesis. Now, we demonstrate that synthetic peptides corresponding to the VDAC1 N-terminal region and selected sequences bound specifically, in a concentrationand time-dependent manner, to immobilized HK-I, as revealed by real time surface plasmon resonance technology. The same VDAC1-based peptides also detached HK bound to brain or tumor-derived mitochondria. Moreover, expression of the VDAC1-based peptides in cells overexpressing HK-I or HK-II prevented HK-mediated protection against staurosporine-induced release of cytochrome c and subsequent cell death. One loop-shaped VDAC1-based peptide corresponding to a selected sequence and fused to a cell-penetrating peptide entered the cell and prevented the anti-apoptotic effects of HK-I and HK-II. This peptide detached mitochondrial-bound HK better than did the same peptide in its linear form. Both cell-expressed and exogenously added cell-penetrating peptide detached mitochondrial-bound HK-I-GFP. These results point to HK-I and HK-II as promoting tumor cell survival through binding to VDAC1, thereby inhibiting cytochrome c release and apoptotic cell death. Moreover, VDAC1-based peptides interfering with HK-mediated anti-apoptotic activity may potentiate the efficacy of conventional chemotherapeutic agents.Cancer cells are characterized by a high rate of glycolysis that serves as their primary energy-generating pathway (1). The molecular basis of this high rate of glycolysis involves a number of genetic and biochemical events, including overexpression of the mitochondria-bound hexokinase isoforms, HK-I 2 and HK-II (1-5). In mammals, HK-I and HK-II are strategically located at the outer membrane of mitochondria, where they gain preferential access to mitochondrially generated ATP (6). In this manner, HK-I and HK-II drive the high glycolytic rates typical of tumor cells, even under aerobic conditions (1, 3). Such elevated levels of mitochondria-bound HK is suggested to play a pivotal role in promoting cell growth and survival in rapidly growing, highly glycolytic tumors and in protecting against mitochondria-mediated cell death (1, 4, 7). The elevated levels of HK-I and HK-II allow tumor cells to evade apoptosis, thereby allowing proliferation to continue (4). Indeed, overexpression of mitochondria-bound HK in the tumor-derived cell line U-937, in T-REx-293, or in vascular smooth muscle cells suppressed staurosporine-induced apoptotic cell death (8, 9). A decrease in apoptotic cell death and concomitant increase in cell proliferation have also been reported to be induced upon HK-II expression in NIH-3T3 (7), rat 1a fibroblasts (10), and WEHI 7.1 cells (11). In addition, binding of HK-II to mitochondria inhibited Bax-induced cytochrome c release and apoptosis (12).Mitochondria-mediated apoptosis results in th...

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Characterization of porin isoforms expressed in tumor cells

Cited by 80 publications

References 31 publications

The Voltage-dependent Anion Channel Is the Target for a New Class of Inhibitors of the Mitochondrial Permeability Transition Pore

The Voltage-dependent Anion Channel Is the Target for a New Class of Inhibitors of the Mitochondrial Permeability Transition Pore

Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

Voltage-dependent Anion Channel 1-based Peptides Interact with Hexokinase to Prevent Its Anti-apoptotic Activity

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