Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1

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. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents. 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. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents. Accumulating evidence indicates that the mitochondrially bound isoforms of hexokinase, HK-I and HK-II, play pivotal roles in promoting cell growth and survival in rapidly growing, highly glycolytic tumors (1Rempel A. Mathupala S.P. Griffin C.A. Hawkins A.L. Pedersen P.L. Cancer Res. 1996; 56: 2468-2471PubMed Google Scholar). As such, HK-I and HK-II were found to be overexpressed in many types of cancer, including colon, prostate, lymphoma, glioma, gastric adenomas, carcinomas, and breast cancers (2Bryson J.M. Coy P.E. Gottlob K. Hay N. Robey R.B. J. Biol. Chem. 2002; 277: 11392-11400Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 3Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev. 2001; 15: 1406-1418Crossref PubMed Scopus (766) Google Scholar, 4Pastorino J.G. Shulga N. Hoek J.B. J. Biol. Chem. 2002; 277: 7610-7618Abstract Full Text Full Text PDF PubMed Scopus (559) Google Scholar, 5Wilson J.E. J. Exp. Biol. 2003; 206: 2049-2057Crossref PubMed Scopus (741) Google Scholar). The elevated levels of HK-I and HK-II allow tumor cells to evade apoptosis, thereby allowing proliferation to continue (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar, 7Pedersen P.L. Mathupala S. Rempel A. Geschwind J.F. Ko Y.H. Biochim. Biophys. Acta. 2002; 1555: 14-20Crossref PubMed Scopus (298) Google Scholar). HK-I and HK-II dock onto the cytosolic surface of the outer mitochondrial membrane mainly through binding to the voltage-dependent anion channel (VDAC) 4The abbreviations used are: VDAC, voltage-dependent anion channel; HK, hexokinase; GFP, green fluorescent protein; FCS, fetal calf serum; PBS, phosphate-buffered saline; FACS, fluorescent-activated cell sorter; PLB, planar lipid bilayer; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; PI, propidium iodide; STS, staurosporine. 4The abbreviations used are: VDAC, voltage-dependent anion channel; HK, hexokinase; GFP, green fluorescent protein; FCS, fetal calf serum; PBS, phosphate-buffered saline; FACS, fluorescent-activated cell sorter; PLB, planar lipid bilayer; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; PI, propidium iodide; STS, staurosporine. (8Nakashima R.A. Mangan P.S. Colombini M. Pedersen P.L. Biochemistry. 1986; 25: 1015-1021Crossref PubMed Scopus (187) Google Scholar). It has been proposed that binding of HK to mitochondria allows a continuous ATP flux, providing energy for the phosphorylation of glucose, and thus an increased glycolytic rate (7Pedersen P.L. Mathupala S. Rempel A. Geschwind J.F. Ko Y.H. Biochim. Biophys. Acta. 2002; 1555: 14-20Crossref PubMed Scopus (298) Google Scholar). VDAC, also known as mitochondrial porin, functions as the major channel allowing passage of nucleotides, ions, Ca2+, and other metabolites between the intermembrane space and cytoplasm (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google Scholar, 10Shoshan-Barmatz V. Israelson A. Brdiczka D. Sheu S.S. Curr. Pharm. Des. 2006; 12: 2249-2270Crossref PubMed Scopus (273) Google Scholar, 11Shoshan-Barmatz V. Gincel D. Cell Biochem. Biophys. 2003; 39: 279-292Crossref PubMed Scopus (168) Google Scholar). In vitro and in vivo studies have shown that HK-I and HK-II play a clear role in protecting against mitochondrially regulated apoptosis through direct interaction with mitochondria (3Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev. 2001; 15: 1406-1418Crossref PubMed Scopus (766) Google Scholar) and, more specifically, with VDAC (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar). Several recent studies demonstrated that in tumor cells, HK-I (12Mathupala S.P. Rempel A. Pedersen P.L. J. Biol. Chem. 1995; 270: 16918-16925Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 13Nakashima R.A. Paggi M.G. Scott L.J. Pedersen P.L. Cancer Res. 1988; 48: 913-919PubMed Google Scholar, 14Rempel A. Bannasch P. Mayer D. Biochim. Biophys. Acta. 1994; 1219: 660-668Crossref PubMed Scopus (75) Google Scholar) and HK-II (15Sade H. Khandre N.S. Mathew M.K. Sarin A. Eur. J. Immunol. 2004; 34: 119-125Crossref PubMed Scopus (21) Google Scholar, 16Preston T.J. Abadi A. Wilson L. Singh G. Adv. Drug Deliv. Rev. 2001; 49: 45-61Crossref PubMed Scopus (91) Google Scholar) not only augment cellular energy supply and levels of glucose 6-phosphate, an intermediate metabolic in many biosynthetic pathways, but also protect against cell death. The molecular mechanisms by which mitochondrially bound HK promotes cell survival are not, however, fully understood. Studies relying on purified VDAC, isolated mitochondria, or cells in culture suggest that the anti-apoptotic activity of HK-I occurs via its interaction with VDAC1 and modulation of the mitochondrial phase of apoptosis (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar). HK-I interacts directly with VDAC to induce channel closure and prevent the release of cytochrome HK-I overexpression in cells against apoptotic cell death induced by either staurosporine (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar) or VDAC1 overexpression H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google Scholar). It has also been shown that of the of HK-II mitochondria via the phosphorylation of VDAC and that the induced by chemotherapeutic increased the binding of HK-II to mitochondria J.G. Hoek J.B. Shulga N. Cancer Res. PubMed Scopus Google Scholar). of VDAC with other including M. Biochim. Biophys. Acta. 2006; PubMed Scopus Google cytochrome c C.A. J. Biol. PubMed Scopus Google the J. PubMed Scopus Google the Brdiczka D. Biochim. 2003; PubMed Scopus Google J. G. M. Biochim. Biophys. Acta. 2006; PubMed Scopus Google and the have also been VDAC proposed to be a of the mitochondrial phase of apoptosis, with its interaction with and the rate of release of intermembrane space that the phase of apoptosis V. Israelson A. Brdiczka D. Sheu S.S. Curr. Pharm. Des. 2006; 12: 2249-2270Crossref PubMed Scopus (273) Google Scholar). of these however, has the interaction of VDAC been The of VDAC has not been Several of evidence point to the that VDAC a by (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google Scholar) or V. A. M. G. M. A. J. Biochem. 2003; Google Scholar) and an by as to the cytoplasm V. A. M. G. M. A. J. Biochem. 2003; Google the membrane (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google or on the membrane surface S. H. M. P. Biochem. Mol. 1995; PubMed Scopus Google Scholar). we have demonstrated that a mutation in by inhibited HK-I interaction with VDAC1 and HK-I-mediated against apoptotic cell death induced by overexpression of native VDAC1 H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google Scholar). In of VDAC1 with HK-I was by of murine VDAC1. In we have two cytoplasmic in the VDAC1 that are required for interaction with HK-I and for HK-I-mediated against cell death via release of cytochrome glucose 6-phosphate, and propidium were was was was was was and against and green were c were were was Cell growth and and the fetal calf and were and were was and J. of was into the for of of mVDAC1 was in vitro by mVDAC1 were the and and in the mVDAC1 served as the for of mVDAC1 or mutated mVDAC1 were into the and of the the and two the to allow for of mVDAC1 in The in which was to the HK-I was an to into the the of in by J. E. by with the and was by and into were by of the used for in in a new cells were an of and in with FCS, and were a of in with PBS, and in cells, a cell were an of and in with FCS, and cell used are of expressing the cells are cells with the and were with and S. S. Shoshan-Barmatz V. S. A. 2006; PubMed Scopus (187) Google Scholar). cells were also with or the of were with and cells were as cells that was with Cell cells were in with FCS, and a of were with or with native or mutated was by with a of a with a were on for and and in of with FCS, and were as by with cells or cells were in in a to In cells were with or by and in with The cells were with or and in the of The of cells was of cell cells were to with and in as previously S. S. Shoshan-Barmatz V. S. A. 2006; PubMed Scopus (187) Google Scholar). The cells were by and were with an a In in which and apoptotic cells were cells were for c by or cells and cells expressing native or the of were on for and were with cells were to for cells were cells were with for and and were were with PBS, for on in and and by a were for and the were for of the as cytosolic were in and by on and c by with and by a the cells were of cells, in the cell was and and HK levels were by and cells were with and with or the cells were to for The cells and growth were for with the cells with PBS, and in of to which of was by to the were for and with The was in of and in and The propidium was to a of and of was a cells or cells expressing native mVDAC1 or the of were on and with cells were with upon for in an which cells were with for were for in the cells were for in Cell was by VDAC and and mVDAC1 was with mitochondria isolated expressing these and purified by on by was by V. Gincel D. Cell Biochem. Biophys. 2003; 39: 279-292Crossref PubMed Scopus (168) Google Scholar). of purified VDAC into a planar lipid bilayer and were as previously D. H. Shoshan-Barmatz V. Biochem. J. 2001; PubMed Scopus Google Scholar). were in with a were was to the or a were into the PLB, the was by of the with of a to prevent were a The were with to the of the membrane The were a and a and was used for were The interaction of HK-I with VDAC and against cell death induced by or VDAC1 overexpression has been demonstrated (3Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev. 2001; 15: 1406-1418Crossref PubMed Scopus (766) Google Scholar, H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar, H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google Scholar). We that its to bind HK-I H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google Scholar). define the and amino involved in the interaction of VDAC1 with HK-I, of mVDAC1 was The of these mVDAC1 on HK-I against cell death were by of native or mutated mVDAC1 in either cells, in cells, the VDAC1 was S. S. Shoshan-Barmatz V. S. A. 2006; PubMed Scopus (187) Google Scholar) or in the cells HK-I. The amino acids to be were on to be to the to VDAC1 membrane proposed (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google Scholar, S. H. M. P. Biochem. Mol. 1995; PubMed Scopus Google Scholar). In were by a to the VDAC known for its to bind HK-I J.E. J. PubMed Scopus Google Scholar). but in the for mVDAC1 with mVDAC1 in HK-I binding H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google not in VDAC1 as as in VDAC, which also to bind HK-I J.E. J. PubMed Scopus Google Scholar). of the amino of the of or murine VDAC1 with the of S. or N. VDAC that in to the amino acids and are not in the these amino acids in the by and VDAC1 overexpression cell death H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google cells were to HK-I and only with or and cell death induced by overexpression of native mVDAC1 or was in cells HK-I, to the other as with cells, of HK-I against cell death was in cells or These results that the cells the of mVDAC1 the anti-apoptotic of HK-I. The anti-apoptotic of HK-I was also in other cell as In we used cells, in which the VDAC1 was that the of but not murine VDAC1 S. S. Shoshan-Barmatz V. S. A. 2006; PubMed Scopus (187) Google Scholar). cells were to or the of The inhibited growth of the cells S. S. Shoshan-Barmatz V. S. A. 2006; PubMed Scopus (187) Google Scholar) was by of or as induced by not induce cell death by mVDAC1 cells expressing native and were to as as to HK-I In cells HK-I, against apoptosis was only in cells or but not in cells of cell the overexpression of HK-I in the cells These results that HK-I interacts with the proposed VDAC1 cytosolic acids the and point to the amino involved in mVDAC1 with amino in the proposed cytosolic HK-I interaction with amino acids in the proposed cytosolic acids and were by to in In the of HK-I overexpression on apoptotic cell death induced by in cells expressing or as induced by were HK-I overexpression against apoptosis in cells expressing or cell death to These results that HK-I protects against cell death induced by and suggest that the proposed cytosolic not involved in the interaction of VDAC1 with HK-I. in the for the of mVDAC1 with of the VDAC1 proposed cytosolic acids in the interaction of the with HK-I was also was was found to be for the interaction of with VDAC1 to prevent apoptotic cell death A. H. Abu-Hamad S. E. Shoshan-Barmatz V. Cell PubMed Scopus Google Scholar). mVDAC1 was overexpressed in cells HK-I, against cell death was in to cells the native mVDAC1 the amino acids in and were by and in cells of and the of HK-I overexpression on apoptotic cell death induced by was HK-I against cell death induced by in cells expressing or but not in cells expressing in in to also for HK-I binding to VDAC1. HK-I-mediated against apoptosis in cells native or but not were propidium The in was by HK-I in cells also expressing native or but not in cells expressing These results are in with apoptosis was by and or by cytochrome c release These results suggest that the interaction of HK-I with mVDAC1 the amino acids in with in the are to the cytoplasm to a proposed (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google Scholar). c by or by HK-I in but we HK-I inhibits cytochrome c release as by in cells expressing native or cells expressing mVDAC1 or the of were to HK-I. The cytochrome c mitochondria to the apoptosis in these cells was by c HK-I overexpression inhibited cytochrome c release in cells expressing native but not HK-I overexpression in cells also inhibited apoptotic cell death and cytochrome c release as induced by or mitochondrial in the cytosolic as the of cytochrome the of VDAC was by not These findings with the of HK-I to protect against cell death induced by in cells expressing and or by and with the of HK-I to with to native but not mutated mVDAC1 reconstituted into a purified native mVDAC1 was reconstituted into a in of as The reconstituted was with HK-I to the to which VDAC was the was to for and, to the channel activity was the purified or was reconstituted into a PLB, and through the VDAC1 channel in to a to were and the of HK-I The the and into a a HK-I interaction of HK-I with VDAC1 was also in of the of HK-I on native or mutated mVDAC1 of HK-I a of on channel of the was for to HK-I inhibited channel activity in a the channel in with of the HK glucose to bound HK, M. Wilson J.E. Biochem. Biophys. PubMed Scopus Google the channel its not not only but also VDAC1 to an channel of with diminished HK-I against cell death was reconstituted into a to in HK-I binding to mVDAC1 and were and the in to a of to were and the of HK-I of purified HK-I to native mVDAC1, the channel was and the channel was in a the other HK-I on the of for to results as with a in channel was These results suggest that for the interaction of VDAC1 with HK-I, required for of the HK-I-VDAC1 Finally, to that HK-I not with in the we the in cells and cells expressing native or and its cellular that in cells, and with a that mitochondria in of was in cells expressing the other in cells expressing was in the and not with These results that HK-I not bind to the as also demonstrated with the purified It has been shown that tumor cells a rate of (7Pedersen P.L. Mathupala S. Rempel A. Geschwind J.F. Ko Y.H. Biochim. Biophys. Acta. 2002; 1555: 14-20Crossref PubMed Scopus (298) Google known to be in to the increased of mitochondrially bound HK-I and HK-II in cells (12Mathupala S.P. Rempel A. Pedersen P.L. J. Biol. Chem. 1995; 270: 16918-16925Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 13Nakashima R.A. Paggi M.G. Scott L.J. Pedersen P.L. Cancer Res. 1988; 48: 913-919PubMed Google Scholar, 14Rempel A. Bannasch P. Mayer D. Biochim. Biophys. Acta. 1994; 1219: 660-668Crossref PubMed Scopus (75) Google Scholar). In vitro and in vivo studies have also shown that HK-I and HK-II play a clear role in protecting cells against mitochondrially regulated apoptosis through direct with VDAC (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar, H. Khandre N.S. Mathew M.K. Sarin A. Eur. J. Immunol. 2004; 34: 119-125Crossref PubMed Scopus (21) Google Scholar, H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google Scholar, J.G. Hoek J.B. Shulga N. Cancer Res. PubMed Scopus Google Scholar). overexpression of HK-I in the cell or cells or VDAC1 apoptotic cell death and against apoptotic cell death has also been in (3Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev. 2001; 15: 1406-1418Crossref PubMed Scopus (766) Google cells M. Paggi M.G. A. Res. 1994; Google and cells (15Sade H. Khandre N.S. Mathew M.K. Sarin A. Eur. J. Immunol. 2004; 34: 119-125Crossref PubMed Scopus (21) Google Scholar). These results suggest that HK-I or HK-II, via interaction with prevent key in mitochondrially mediated apoptosis. It that the of HK required for its interaction with the mitochondria V. Griffin S. A. PubMed Scopus Google Scholar, Wilson J.E. Biochem. Biophys. Scopus Google Scholar, D. Wilson J.E. Biochem. Biophys. PubMed Scopus Google Scholar) and VDAC (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar). the VDAC1 with HK-I or HK-II As such, has VDAC1 amino acids and for HK-I binding and the against cell death. VDAC1 to the of HK-I or of VDAC1 has not been of the VDAC1 however, to the of the of the a and or bilayer (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google Scholar, V. G. Biochemistry. PubMed Scopus Google Scholar). These are by of on of the membrane that of interaction for including HK-I and The that a point or binding of HK-I to mutated VDAC1 reconstituted into a bilayer or in cells and the of HK-I against cell death induced by overexpression of VDAC1 in or cells H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google and and to the as the or of by the findings that of the VDAC1 with HK binding to mitochondria (8Nakashima R.A. Mangan P.S. Colombini M. Pedersen P.L. Biochemistry. 1986; 25: 1015-1021Crossref PubMed Scopus (187) Google Scholar, V. J. Biol. Chem. Full Text PDF PubMed Google as as HK-I-mediated inhibition of cytochrome c release into the of the interaction of HK-I and with VDAC1 to a in VDAC but not of the channel Shoshan-Barmatz V. Eur. J. Biochem. PubMed Scopus Google Scholar, V. N. M. 1996; PubMed Scopus Google Scholar) and the of in that the not in VDAC are by to studies have proposed that the of the as a in and N. VDAC J. E. M. Colombini M. Biophys. J. Full Text Full Text PDF PubMed Scopus Google Scholar, L. E. Colombini M. M. S. A. PubMed Scopus Google Scholar). to of the proposed VDAC1 in the of the cytoplasmic (9Colombini M. Mol. Cell Biochem. 2004; 256-257: 107-115Crossref PubMed Google Scholar). other amino acids in proposed were and the of on HK-I binding to purified VDAC1 and HK-I against cell death were The that other amino residues, and are for HK-I binding to VDAC1 and against cell death to as with HK-I. and proposed mVDAC1 was also found to be involved in the interaction of HK-I with mVDAC1 and in the against cell death by HK-I The that the of to bind HK-I a that the required for of the interaction between HK-I and VDAC1. It be that as was also found to be for the interaction of with VDAC1 and protecting against cell death A. H. Abu-Hamad S. E. Shoshan-Barmatz V. Cell PubMed Scopus Google Scholar). The of HK-I or HK-II with VDAC1 was to a amino found in the of HK-I and HK-II, an role an of the interaction V. Griffin S. A. PubMed Scopus Google Scholar, Wilson J.E. Biochem. Biophys. Scopus Google Scholar). of HK-I interaction of the with VDAC (6Azoulay-Zohar H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar, Wilson J.E. Biochem. Biophys. Scopus Google Scholar). The role of the HK-I in the mitochondrial of the was also demonstrated to HK-I binding to mitochondria S. L. A. 2004; Google Scholar). Our results, however, the amino acids and in VDAC1 involved in the with HK-I the and VDAC1 The of the and may be to the of HK binding to mitochondria on ions, proposed to direct between HK and the surface of the outer mitochondrial membrane via or other E. Biochem. Biophys. PubMed Scopus Google Scholar, P.L. Wilson J.E. Biochem. Biophys. PubMed Scopus Google Scholar). has been proposed to a between on HK-I and the outer mitochondrial membrane P.L. Wilson J.E. Biochem. Biophys. PubMed Scopus Google Scholar) or may a specific HK and In the interaction of HK-I with VDAC1 bilayer or in isolated however, or HK-I bound to VDAC1. It has been shown that inhibits apoptosis by promoting the binding of HK-II to the mitochondria (3Gottlob K. Majewski N. Kennedy S. Kandel E. Robey R.B. Hay N. Genes Dev. 2001; 15: 1406-1418Crossref PubMed Scopus (766) Google Scholar). of was shown to be mediated by regulation of VDAC to bind HK-II that the mitochondria and thus allows apoptosis J.G. Hoek J.B. Shulga N. Cancer Res. PubMed Scopus Google Scholar). of c by of has been to its to and D. Rev. Drug PubMed Scopus Google Scholar). recent studies suggest that mitochondria are also of L. J. 39: PubMed Scopus Google Scholar, Cancer Res. 2006; 12: PubMed Scopus Google Scholar). was found to induce mitochondrial in cells and the release of cytochrome c the mitochondria to the G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) mitochondria isolated cells of the and cell Cancer Res. 2006; 12: PubMed Scopus Google Scholar). In an of was found to apoptosis of cells in J. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). has been demonstrated that interacts directly with It was demonstrated that the of bound to VDAC more the bound by cellular Cancer Res. 2006; 12: PubMed Scopus Google Scholar). In cells of the cell cell were to the of VDAC1 was found to be by a of with of mechanisms to protect cells A. P. H. M. P. 2004; PubMed Scopus Google Scholar). Our results that cytochrome c release and apoptotic cell death that be inhibited by HK-I suggest that the mitochondrially mediated the of HK-I to protect against cytochrome c release in cells expressing mutated that VDAC1 involved in of apoptosis. these findings that the mitochondrially a role in the of the interaction of HK-I with the two proposed VDAC1 cytosolic in HK-I-mediated inhibition of cytochrome c release and and H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar) and in the of HK-I against apoptotic cell death and and H. Israelson A. Abu-Hamad S. Shoshan-Barmatz V. Biochem. J. 2004; 377: 347-355Crossref PubMed Scopus (334) Google Scholar, H. Abu-Hamad S. Israelson A. Shoshan-Barmatz V. Cell 12: PubMed Scopus Google Scholar). inhibition of HK-I or HK-II interaction with VDAC may mitochondrial apoptotic these results the of VDAC1 in mitochondrially mediated apoptosis. these findings to the of peptides the two VDAC1 as to potentiate the efficacy of conventional chemotherapeutic agents. and HK-II and and are levels in many types of (7Pedersen P.L. Mathupala S. Rempel A. Geschwind J.F. Ko Y.H. Biochim. Biophys. Acta. 2002; 1555: 14-20Crossref PubMed Scopus (298) Google Scholar, 14Rempel A. Bannasch P. Mayer D. Biochim. Biophys. Acta. 1994; 1219: 660-668Crossref PubMed Scopus (75) Google Scholar, Rev. 2004; PubMed Scopus Google Scholar). these VDAC1 peptides to tumor cells anti-apoptotic may thus an via a of the mechanisms of the cells, thereby promoting apoptosis. the of peptides were to be with chemotherapeutic to be

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