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  • Original Paper
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Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437

Abstract

An increasing number of experimental chemotherapeutic agents induce apoptosis by directly triggering mitochondrial membrane permeabilization (MMP). Here we examined MMP induced by lonidamine, arsenite, and the retinoid derivative CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were strongly protected against the MMP-inducing and apoptogenic effects of lonidamine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effect on protein-free liposomes. The ANT-dependent membrane permeabilization was inhibited by the two ANT ligands ATP and ADP, as well as by recombinant Bcl-2 protein. Lonidamine, arsenite, and CD437, added to synthetic planar lipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20±7, 100±30, and 47±7 pS, respectively. Altering the ATP/ADP gradient built up on the inner mitochondrial membrane by inhibition of glycolysis and/or oxidative phosphorylation differentially modulated the cytocidal potential of lonidamine, arsenite, and CD437. Inhibition of F0F1ATPase without glycolysis inhibition sensitized to lonidamine-induced cell death. In contrast, only the combined inhibition of glycolysis plus F0F1ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depletion and/or oligomycin addition. These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds.

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Abbreviations

ANT:

adenine nucleotide translocator

AIF:

apoptosis inducing factor

Ars:

arsenic trioxide

Atr:

atractyloside

CD437:

6[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid

Diamide:

diazenedicarboxylic acid bis 5N, N-dimethylamide, DiOC6(3), 3,3′dihexyloxacarbocyanine iodide

ΔΨm:

mitochondral transmembrane potential

HE:

hydroethidine

LND:

lonidamine

MMP:

mitochondrial membrane permeabilization

4-MU:

4-methylumbelliferone

4-MUP:

4-methylumbelliferylphosphate

PI:

propidium iodide

ROS:

reactive oxygen species

VDAC:

voltage-dependent anion channel

vMIA:

viral mitochondria-localized inhibitor of apoptosis

Vpr:

viral protein R

References

  • Aillet F, Masutani H, Elbim C, Raoul H, Chene L, Nugeyre MT, Paya C, Barre-Sinoussi F, Gougerot-Pocidalo MA, Israel N . 1998 J. Virol. 72: 9698–9705

  • Andre N, Braguer D, Brasseur G, Goncalves A, Lemesle-Meunier D, Guise S, Jordan MA, Briand C . 2000 Cancer Res. 60: 5349–5353

  • Bauer MKA, Schubert A, Rocks O, Grimm S . 1999 J. Cell. Biol. 147: 1493–1501

  • Belzacq A-S, Jacotot E, Vieira HLA, Mistro D, Granville DJ, Xie ZH, Reed JC, Kroemer G, Brenner C . 2001 Cancer Res. 61: 1260–1264

  • Brenner C, Cadiou H, Vieira HLA, Zamzami N, Marzo I, Xie Z, Leber B, Andrews D, Duclohier H, Reed JC, Kroemer G . 2000 Oncogene 19: 329–336

  • Brustovetsky N, Klingenberg M . 1996 Biochemistry 35: 8483–8488

  • Colberg-Poley AM, Patel MB, Erezo DP, Slater JE . 2000 J. Gen. Virol. 7: 1779–1789

  • Costantini P, Belzacq A-S, Vieira HLA, Larochette N, de Pablo M, Zamzami N, Susin SA, Brenner C, Kroemer G . 2000a Oncogene 19: 307–314

  • Costantini P, Jacotot E, Decaudin D, Kroemer G . 2000b J. Natl. Cancer Inst. 92: 1042–1053

  • Ferri KF, Jacotot E, Blanco J, Esté JA, Zamzami A, Susin SA, Brothers G, Reed JC, Penninger JM, Kroemer G . 2000 J. Exp. Med. 192: 1081–1092

  • Fulda S, Scaffidi C, Susin SA, Krammer PH, Kroemer G, Peter ME, Debatin KM . 1998a J. Biol. Chem. 273: 33942–33948

  • Fulda S, Susin SA, Kroemer G, Debatin KM . 1998b Cancer Res. 58: 4453–4460

  • Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, Carson DA, Leoni LM . 2000 Blood 96: 3537–3543

  • Goldmacher VS, Bartle LM, Skletskaya S, Dionne CA, Kedersha NL, Vater CA, Han JW, Lutz RJ, Watanabe S, McFarland EDC, Kieff ED, Mocarski ES, Chittenden T . 1999 Proc. Natl. Acad. Sci. USA 96: 12536–12541

  • Green DR, Kroemer G . 1998 Trends Cell. Biol. 8: 267–271

  • Green DR, Reed JC . 1998 Science 281: 1309–1312

  • Hirsch T, Decaudin D, Susin SA, Marchetti P, Larochette N, Resche-Rigon M, Kroemer G . 1998 Exp. Cell. Res. 241: 426–434

  • Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, Geuskens M, Kroemer G . 1997 Oncogene 15: 1573–1582

  • Jacotot E, Ferri KF, El Hamel C, Brenner C, Druillenec S, Hoebeke J, Rustin P, Métivier D, Lenoir C, Geuskens M, Vieira HLA, Loeffler M, Belzacq A-S, Briand J-P, Zamzami N, Edelman L, Xie ZH, Reed JC, Roques BP, Kroemer G . 2001 J. Exp. Med. 193: 509–520

  • Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CYJ, Sasaki T, Elia AJ, Cheng H-YM, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong Y-Y, Zuñiga-Pflücker JC, Kroemer G, Penninger JM . 2001 Nature 410: 549–554

  • Klingenberg M . 1980 J. Membrane Biol. 56: 97–105

  • Kroemer G . 1997 Nat. Med. 3: 614–620

  • Kroemer G, Dallaporta B, Resche-Rigon M . 1998 Annu. Rev. Physiol. 60: 619–642

  • Kroemer G, de Thé H . 1999 J. Nat. Cancer Inst. 91: 743–745

  • Kroemer G, Reed JC . 2000 Nat. Med. 6: 513–519

  • Larochette N, Decaudin D, Jacotot E, Brenner C, Marzo I, Susin SA, Zamzami N, Xie Z, Reed JC, Kroemer G . 1999 Exp. Cell. Res. 249: 413–421

  • Leist M, Single B, Castoldi AF, Kühnle S, Nicotera P . 1997 J. Exp. Med. 185: 1481–1486

  • Liu XS, Kim CN, Yang J, Jemmerson R, Wang X . 1996 Cell 86: 147–157

  • Loeffler M, Daugas E, Susin SA, Zamzami N, Métivier D, Nieminen A-L, Brothers G, Penninger JM, Kroemer G . 2001 FASEB J. 15: 758–767

  • Marchetti P, Zamzami N, Josph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin SA, Kroemer G, Formstecher P . 1999 Cancer Res. 54: 6257–6275

  • Martin DS, Bertino JR, Koutcher JA . 2001 Cancer Res. 60: 6776–6783

  • Martinou J-C, Green DR . 2001 Nat. Rev. Mol. Cell. Biol. 2: 63–67

  • Marzo I, Brenner C, Zamzami N, Jürgensmeier J, Susin SA, Vieira HLA, Prévost M-C, Xie Z, Matsuyama S, Reed JC, Kroemer G . 1998 Science 281: 2027–2031

  • Montal M, Mueller P . 1972 Proc. Natl. Acad. Sci. USA 69: 3561–3566

  • Nicoletti I, Migliorati G, Pagliacci MC, Riccardi C . 1991 J. Immunol. Meth. 139: 271–280

  • Ravagnan L, Marzo I, Costantini P, Susin SA, Zamzami N, Petit PX, Hirsch F, Poupon M-F, Miccoli L, Xie Z, Reed JC, Kroemer G . 1999 Oncogene 18: 2537–2546

  • Rippo MR, Malisan F, Ravagnan L, Condo I, Tomassini B, Costantini P, Todaro M, Susin SA, Rufini A, Kroemer G, Testi R . 2000 FASEB J. 14: 2047–2054

  • Saito M, Korsmeyer SJ, Schlesinger PH . 2000 Nat. Cell. Biol. 2: 553–555

  • Shimizu S, Ide T, Yanagida T, Tsujimoti Y . 2000 J. Biol. Chem. 275: 12321–12325

  • Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP . 1998 New Engl. J. Med. 339: 1341–1348

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G . 1999 Nature 397: 441–446

  • Tinhofer I, Bernard D, Senfter M, Anether G, Loeffler G, Kroemer G, Kofler R, Csordas A, Greil R . 2001 FASEB J. 15: 1613–1615

  • Vieira HL, Belzacq A-S, Haouzi D, Bernassola F, Cohen I, Jacotot E, Ferri KF, Hamel EH, Bartle LM, Melini G, Brenner C, Goldmacher V, Kroemer G . 2001 Oncogene 20: 4305–4316

  • Vieira HL, Haouzi D, El Hamel C, Belzacq A-S, Brenner C, Kroemer G . 2000 Cell Death Differ. 7: 1146–1154

  • Vogelstein B, Lane D, Levine AJ . 2000 Nature 408: 307–310

  • Watabe M, Machida K, Osada H . 2000 Cancer Res. 60: 5214–5222

  • Xie ZH, Schendel S, Matsuyama S, Reed JC . 1998 Biochemistry 37: 6410–6418

  • Zamzami N, El Hamel C, Muñoz C, Brenner C, Belzacq A-S, Costantini P, Molle G, Kroemer G . 2000 Oncogene 19: 6342–6350

  • Zamzami N, Kroemer G . 2001 Nat. Rev. Mol. Cell. Biol. 2: 67–71

  • Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G . 1995 J. Exp. Med. 182: 367–377

  • Zamzami N, Marzo I, Susin SA, Brenner C, Larochette N, Marchetti P, Reed J, Kofler R, Kroemer G . 1998 Oncogene 16: 1055–1063

  • Zoratti M, Szabò I . 1995 Biochem. Biophys. Acta - Rev. Biomembranes 1241: 139–176

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Acknowledgements

We thank Dr V Goldmacher (Immunogen Inc, Cambridge, MA, USA) for vMIA transfected Hela cells and critical reading of the manuscript, Dr N Israel (Pasteur Institute, Paris) for Bcl-2 transfected Jurkat cells, Z Xie and JC Reed (Burnham Institute, La Jolla, CA, USA) for recombinant Bcl-2, the Angelini Research Institute (Rome, Italy) for LND, Galderma (Sophia Antipolis, France) for CD437 gift, D Decaudin and MF Poupon for technical advice. This work has been supported by a special grant from the Ligue Nationale contre le Cancer as well as by grants from ANRS (to G Kroemer), FRM (to G Kroemer and C Brenner), Association pour la Recherche sur le Cancer (to C Brenner), French Ministry of Science (to C Brenner), and the European Commission (QLG1-1999-00739 to G Kroemer). HLA Vieira receives a fellowship from the Fundação para a Ciência e a Tecnologia PRAXIS XXI, Portugal; A-S Belzacq from ARC, CE Hamel from the Ligue contre le Cancer, Val de Marne, I Cohen and D Haouzi from the Ligue Nationale contre le Cancer.

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Correspondence to Guido Kroemer.

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Belzacq, AS., El Hamel, C., Vieira, H. et al. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20, 7579–7587 (2001). https://doi.org/10.1038/sj.onc.1204953

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