Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells

Oncogene volume 23, pages 39–48 (2004)Cite this article

Abstract

The inhibitor of apoptosis (IAP) protein Survivin is expressed in most cancers and is a key factor in maintaining apoptosis resistance. Although several IAPs have been shown to act as direct inhibitors of caspases, the precise antiapoptotic function of Survivin remains controversial. To clarify the mechanism by which Survivin protects cells, we investigated the kinetics of apoptosis and apoptotic events following Survivin inhibition utilizing a melanoma cell line harboring a tetracycline-regulated Survivin dominant-negative mutant (Survivin-T34A). Blocking Survivin resulted in both caspase activation and apoptosis; however, the level of apoptosis was only partially reduced by caspase inhibition. Survivin blockade also resulted in mitochondrial events that preceded caspase activation, including depolarization and release of cytochrome c and Smac/DIABLO. Levels of other IAPs were not altered in Survivin-targeted cells, although modest cleavage of XIAP and Livin was observed. The earliest proapoptotic event observed in Survivin-targeted cells was nuclear translocation of mitochondrial apoptosis-inducing factor (AIF), known to trigger both apoptotic mitochondrial events and caspase-independent DNA fragmentation. These findings suggest that a key antiapoptotic function of Survivin relates to inhibition of mitochondrial and AIF-dependent apoptotic pathways, and its expression in melanoma and other cancers likely protects against both caspase-independent and -dependent apoptosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

Abbreviations

AIF:

apoptosis-inducing factor

IAP:

inhibitor of apoptosis

tet:

tetracycline

UVB:

ultraviolet-B

z-VAD-fmk:

z-Val-Ala-Asp(OMe)-fluoromethyl ketone

References

  • Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J and Altieri DC . (1998). Am. J. Pathol., 152, 43–49.

  • Altieri DC . (2001). Trends Mol. Med., 7, 542–547.

  • Altieri DC . (2003). Nat. Rev. Cancer, 3, 46–54.

  • Altieri DC, Marchisio PC and Marchisio C . (1999). Lab. Invest., 79, 1327–1333.

  • Ambrosini G, Adida C and Altieri DC . (1997). Nat. Med., 3, 917–921.

  • Ashkenazi A and Dixit VM . (1998). Science, 281, 1305–1308.

  • Banks DP, Plescia J, Altieri DC, Chen J, Rosenberg SH, Zhang H and Ng SC . (2000). Blood, 96, 4002–4003.

  • Borner C and Monney L . (1999). Cell Death Differ., 6, 497–507.

  • Bossy-Wetzel E and Green DR . (1999). J. Biol. Chem., 274, 17484–17490.

  • Bowen AR, Hanks AN, Allen SM, Alexander A, Diedrich MJ and Grossman D . (2003). J. Invest. Dermatol., 120, 48–55.

  • Chantalat L, Skoufias DA, Kleman JP, Jung B, Dideberg O and Margolis RL . (2000). Mol. Cell, 6, 183–189.

  • Conway EM, Pollefeyt S, Cornelissen J, DeBaere I, Steiner-Mosonyi M, Ong K, Baens M, Collen D and Schuh AC . (2000). Blood, 95, 1435–1442.

  • Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prevost MC, Leber B, Andrews D, Penninger J and Kroemer G . (2000). FASEB J., 14, 729–739.

  • Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS and Reed JC . (1999). EMBO J., 18, 5242–5251.

  • Deveraux QL and Reed JC . (1999). Genes Dev., 13, 239–252.

  • Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC . (1998). EMBO J., 17, 2215–2223.

  • Deveraux QL, Takahashi R, Salvesen GS and Reed JC . (1997). Nature, 388, 300–304.

  • Du C, Fang M, Li Y, Li L and Wang X . (2000). Cell, 102, 33–42.

  • Fortugno P, Wall NR, Giodini A, O'Connor DS, Plescia J, Padgett KM, Tognin S, Marchisio PC and Altieri DC . (2002). J. Cell Sci., 115, 575–585.

  • Green DR . (1998). Cell, 94, 695–698.

  • Green DR and Reed JC . (1998). Science, 281, 1309–1312.

  • Grossman D, Kim PJ, Blanc-Brude OP, Brash DE, Tognin S, Marchisio PC and Altieri DC . (2001a). J. Clin. Invest., 108, 991–999.

  • Grossman D, Kim PJ, Schechner JS and Altieri DC . (2001b). Proc. Natl. Acad. Sci. USA, 98, 635–640.

  • Grossman D, McNiff JM, Li F and Altieri DC . (1999a). J. Invest. Dermatol., 113, 1076–1081.

  • Grossman D, McNiff JM, Li F and Altieri DC . (1999b). Lab. Invest., 79, 1121–1126.

  • Harlin H, Reffey SB, Duckett CS, Lindsten T and Thompson CB . (2001). Mol. Cell. Biol., 21, 3604–3608.

  • Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zuniga-Pflucker JC, Kroemer G and Penninger JM . (2001). Nature, 410, 549–554.

  • Kasof GM and Gomes BC . (2001). J. Biol. Chem., 276, 3238–3246.

  • Kerr JF, Wyllie AH and Currie AR . (1972). Br. J. Cancer, 26, 239–257.

  • Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC and Altieri DC . (1999). Nat. Cell Biol., 1, 461–466.

  • Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC and Altieri DC . (1998). Nature, 396, 580–584.

  • Mahotka C, Wenzel M, Springer E, Gabbert HE and Gerharz CD . (1999). Cancer Res., 59, 6097–6102.

  • Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, Davoodi J, Rasper D, Roy S, Slack RS, Nicholson DW and MacKenzie AE . (2002). J. Neurosci., 22, 2035–2043.

  • Mate MJ, Ortiz-Lombardia M, Boitel B, Haouz A, Tello D, Susin SA, Penninger J, Kroemer G and Alzari PM . (2002). Nat. Struct. Biol., 9, 442–446.

  • Mesri M, Wall NR, Li J, Kim RW and Altieri DC . (2001). J. Clin. Invest., 108, 981–990.

  • Miramar MD, Costantini P, Ravagnan L, Saraiva LM, Haouzi D, Brothers G, Penninger JM, Peleato ML, Kroemer G and Susin SA . (2001). J. Biol. Chem., 276, 16391–16398.

  • Muchmore SW, Chen J, Jakob C, Zakula D, Matayoshi ED, Wu W, Zhang H, Li F, Ng SC and Altieri DC . (2000). Mol. Cell, 6, 173–182.

  • O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC and Altieri DC . (2000). Proc. Natl. Acad. Sci. USA, 97, 13103–13107.

  • Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA and Zangemeister-Wittke U . (2000). Cancer Res., 60, 2805–2809.

  • Reed JC . (1999). J. Clin. Oncol., 17, 2941–2953.

  • Reed JC . (2000). Am. J. Pathol., 157, 1415–1430.

  • Reed JC . (2001). J. Clin. Invest., 108, 965–969.

  • Reed JC . (2003). Cancer Cell, 3, 17–22.

  • Reutelingsperger CP and van Heerde WL . (1997). Cell. Mol. Life Sci., 53, 527–532.

  • Ricci JE, Gottlieb RA and Green DR . (2003). J. Cell Biol., 160, 65–75.

  • Roy N, Deveraux QL, Takahashi R, Salvesen GS and Reed JC . (1997). EMBO J., 16, 6914–6925.

  • Shankar SL, Mani S, O'Guin KN, Kandimalla ER, Agrawal S and Shafit-Zagardo B . (2001). J. Neurochem., 79, 426–436.

  • Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK and Oh BH . (2001). Biochemistry, 40, 1117–1123.

  • Shockett P, Difilippantonio M, Hellman N and Schatz DG . (1995). Proc. Natl. Acad. Sci. USA, 92, 6522–6526.

  • Sperandio S, de Belle I and Bredesen DE . (2000). Proc Natl. Acad. Sci. USA, 97, 14376–14381.

  • Strasser A, O'Connor L and Dixit VM . (2000). Annu. Rev. Biochem., 69, 217–245.

  • 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 and Kroemer G . (1999). Nature, 397, 441–446.

  • Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T and Reed JC . (1998). Cancer Res., 58, 5315–5320.

  • Thornberry NA and Lazebnik Y . (1998). Science, 281, 1312–1316.

  • Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook BP, Dufault MR, Ferguson AT, Gao Y, He T-C, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K, Zawel L, Zhang W, Zhang X, Zhou W, Haluska FG, Jen J, Sukumar S, Landes GM, Riggins GJ, Vogelstein B and Kinzler KW . (1999). Nat. Genet., 23, 387–388.

  • Verdecia MA, Huang H, Dutil E, Kaiser DA, Hunter T and Noel JP . (2000). Nat. Struct. Biol., 7, 602–608.

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.

  • Wang X, Yang C, Chai J, Shi Y and Xue D . (2002). Science, 298, 1587–1592.

  • Yang Y, Fang S, Jensen JP, Weissman AM and Ashwell JD . (2000). Science, 288, 874–877.

  • Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G and Wu H . (2002). Nat. Struct. Biol., 9, 680–684.

  • Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM and Dawson VL . (2002). Science, 297, 259–263.

  • Zamzami N, El Hamel C, Maisse C, Brenner C, Munoz-Pinedo C, Belzacq AS, Costantini P, Vieira H, Loeffler M, Molle G and Kroemer G . (2000). Oncogene, 19, 6342–6350.

Download references

Acknowledgements

We thank Laura Hoffman for help with fluorescence microscopy, Dr Gary Kasof for Livin antibody, Dr Yuri Lazebnik for Apaf-1 antibody, and Dr Ray Lee for helpful discussions and critically reviewing the manuscript. This work was supported by NIH Grant KO8AR48618, the Huntsman Cancer Foundation, and a Fellowship-to-Faculty Transition Award from the University of Utah funded in part by the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Huntsman Cancer Institute, University of Utah, Salt Lake City, 84112, UT, USA

    Tong Liu & Douglas Grossman

  2. Department of Dermatology, University of Utah, Salt Lake City, 84132, UT, USA

    Brook Brouha & Douglas Grossman

  3. Department of Oncological Sciences, University of Utah, Salt Lake City, 84112, UT, USA

    Douglas Grossman

Authors
  1. Tong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brook Brouha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas Grossman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, T., Brouha, B. & Grossman, D. Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells. Oncogene 23, 39–48 (2004). https://doi.org/10.1038/sj.onc.1206978

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206978

Keywords

This article is cited by

Search

Advanced search

Quick links