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. 2007 May 1;9(2):360–372. doi: 10.1111/j.1582-4934.2005.tb00361.x

Survivin as a target for new anticancer interventions

Nadia Zaffaroni 1,✉, Marzia Pannati 1, Maria Grazia Diadone 1
PMCID: PMC6740253  PMID: 15963255

Abstract

Survivin is a member of the inhibitor of apoptosis protein (IAP) family, that has been implicated in both control of cell division and inhibition of apoptosis. Specifically, its anti‐apoptosis function seems to be related to the ability to directly or indirectly inhibit caspases. Survivin is selectively expressed in the most common human neoplasms and appears to be involved in tumour cell resistance to some anticancer agents and ionizing radiation. On the basis of these findings survivin has been proposed and and attractive target for new anticancer interventions. Several preclinical studies have demonstrated that down‐regulation of survivin expression/function, accomplished through the use of antisense oligonucleotides, dominant negative mutants, ribozymes, small interfering RNAs and cyclin‐dependent kinase inhibitors, increased the apoptotic rate, reduced tumor‐growth potential and sensitized tumor cells to chemotherapeutic drugs with different action mechanisms and γ‐irradiation in in vitro and in vivo models of different human tumor types.

Keywords: Survivin, apoptosis, anticancer drugs, ionizing radiation, antisense oligonucleotides, dominant negative mutants, ribozymes, small interfering RNAs, cycle‐dependent kinase inhinitors

References

  • 1. Reed JC. Apoptosis‐regulating proteins as targets for drug discovery. Trends Mol Med. 2001; 7: 314–9. [DOI] [PubMed] [Google Scholar]
  • 2. Borst P, Bort J, Smets LA, Does resistance to apoptosis affect clinical response to antitumor drugs Drug Res Up. 2001; 4: 129–31. [DOI] [PubMed] [Google Scholar]
  • 3. Schmitt CA, Lowe SW. Apoptosis is critical for drug response in vivo. Drug Res Up. 2001; 4: 132–4. [DOI] [PubMed] [Google Scholar]
  • 4. Yuan J. Transducing signals of life and death. Curr Opin Cell Biol. 1997; 9: 247–51. [DOI] [PubMed] [Google Scholar]
  • 5. Cryns V, Yuan Y. Proteases to die for. Genes Develop.. 1999; 12: 1551–70. [DOI] [PubMed] [Google Scholar]
  • 6. Adams JM, Cory S. The Bcl‐2 protein family: arbiters of cell survival. Science 1998; 281: 1322–6. [DOI] [PubMed] [Google Scholar]
  • 7. Deveraux QL, Reed JC. IAP family proteins‐suppressors of apoptosis. Gen Develop. 1999; 13: 239–52. [DOI] [PubMed] [Google Scholar]
  • 8. Ambrosini G, Adida C, Sirugo A, Altieri DC. Induction of apoptosis and inhibition of cell proliferation by survivin gene targetting. J Biol Chem. 1998; 273: 11177–82. [DOI] [PubMed] [Google Scholar]
  • 9. Ambrosini G, Adida C, Altieri DC. A novel anti‐apoptosis gene, survivin, expressed in cancer and laymphoma. Nat Med. 1997; 3: 917–21. [DOI] [PubMed] [Google Scholar]
  • 10. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE. The inhibitors of apoptosis (IAPs) and thier emerging role in cancer. Oncogene 1998; 17: 3247–59. [DOI] [PubMed] [Google Scholar]
  • 11. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD. Survivin‐δEx3 and survivin‐2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res. 1999; 59: 6097–102. [PubMed] [Google Scholar]
  • 12. Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T, Inuzuka M. Identification of novel splice variant of the human anti‐apoptosis gene survivin. Biochem Biophys Res Commun. 2004; 314: 902–7. [DOI] [PubMed] [Google Scholar]
  • 13. Caldas H, Honsey LE, Altura RA. Survivin 2alpha: a novel Survivin splice variant expressed in human malignancies. Mol Cancer 2005; 4: 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Caldas H, Jiang Y, Holloway MP, Fangusaro J, Mahotka C, Conway EM, Altura RA. Survivin splice variants regulate the balance between proliferation and cell death. Oncogene. 2005; 24: 1994–2007. [DOI] [PubMed] [Google Scholar]
  • 15. Li F, Altieri DC. The cancer anti‐apoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle‐dependent expression. Cancer Res. 1999; 59: 3143–51. [PubMed] [Google Scholar]
  • 16. O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC, Altieri DC. Reglation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA. 2000; 97: 13103–07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Fortugno P, Wall NR, Giodini A, O'Connor DS, Plescia J, Padgett KM, Tognin S, Marchisio PC, Altieri DC. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J Cell Sci. 2002; 115: 575–85. [DOI] [PubMed] [Google Scholar]
  • 18. Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaus DL, Choo KH. Survivin and the inner centromere protein INCENP show similar cell‐cycle localization and gene knockout phenotype. Curr Biol. 2000; 10: 1319–28. [DOI] [PubMed] [Google Scholar]
  • 19. Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC, Altieri DC. Pleiotropic cell‐division defects and apoptosis induced by interference with survivin function. Nat Cell Biol. 1999; 1: 461–6. [DOI] [PubMed] [Google Scholar]
  • 20. Chen J, Wu W, Tahir SK, Kroeger PE, Rosenberg SH, Cowsert LM, Bennett F, Krajewski S, Krajewska M, Welsh K, Reed JC, Ng SC. Down‐regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchroage‐dependent growth. Neoplasia. 2000; 2: 235–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Giodini A, Kallio MJ, Wall NR, Gorbsky GJ, Tognin S, Machisio PC, Altieri DC. Regulation of microtubule stability and mitotic progression by survivin. Cancer Res. 2002; 62: 2462–7. [PubMed] [Google Scholar]
  • 22. Kallio MJ, Neiminen M, Eriksson JE. Human inhibitor of apoptosis protein (IAP) survivin participates in regulation of chromosome segregation and mitotic exit. FASEB. 2001; 15: 2721–23. [DOI] [PubMed] [Google Scholar]
  • 23. Carvalho A, Carmena M, Sambade C, Earnshaw WC, Wheatley SP. Survivin is required for stable check point activation in taxol‐treated HeLa cells. J Cell Sci. 2003; 116: 2987–98. [DOI] [PubMed] [Google Scholar]
  • 24. Dohi T, Beltrami E, Wall NR, Plescia J, Altieri DC. Mitochonrial survivin inhibits apoptosis and promotes tumorigenesis. J Clin Invest. 2004; 114: 1117–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Song Z, Yao X, Wu M. Direct interacton between survivin and Smac/DIABLO is essential for the anti‐apoptotic activity of survivin during taxol‐induced apoptosis. J Biol Chem. 2003; 278: 23130–40. [DOI] [PubMed] [Google Scholar]
  • 25. Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC, Sessa WC, Altieri DC. Regualtion of survivin function by Hsp90. Proc Natl Acad Sci USA. 2003; 100: 13791–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene; 2003; 22: 8581–9. [DOI] [PubMed] [Google Scholar]
  • 27. O'Connor DS, Schechner JS, Adida C, Mesri M, Rothermel AL, Li F, Nath AK, Pober JS, Altieri DC. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol. 2000; 156: 393–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook Bp, Dufault M., Ferguson AT, Gao Y, He TC, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K, Zawel L, Kinzler KW. Analysis of human transcriptomes, Nat Gen. 1999; 23: 387–8. [DOI] [PubMed] [Google Scholar]
  • 29. Plantaz D, Mohapatra G, Matthay KK, Pellarin M, Seeger RC, Feuerstein BG. Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. Am J Pathol. 1997; 150: 81–9. [PMC free article] [PubMed] [Google Scholar]
  • 30. Hattori M, Sakamoto H, Satoh K, Yamamoto T. DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c‐erbB‐2 and survivin genes. Cancer Lett. 2001; 169: 155–64. [DOI] [PubMed] [Google Scholar]
  • 31. Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, Wen SF, Wang L, Kirschmeier P, Bishop WR, Nielsen L, Pickett CB, Liu S. Human survivin is negatively regulated by wild‐type p53 and participates in p53‐dependent apoptotic pathway. Oncogene. 2002; 21: 2613–22. [DOI] [PubMed] [Google Scholar]
  • 32. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J, Dombret H, Reyes F, Diebold J, Gisselbrecht C, Salles G, Altieri DC, Molina TJ. Prognostic significance of survivin expression in diffuse large B‐cell lymphomaas. Blood 2000; 96: 1921–1925. [PubMed] [Google Scholar]
  • 33. Martinez A, Bellosillo B, Bosch F, Ferrer A, Marce S, Villamor N, Ott G, Montserrat E, Campo E. Colomer D. Nuclear survivin expression in mantle cell lymphoma is associated with cell proliferation and survival. Am J Pathol. 2004; 164: 501–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Adida C, Recher C, Raffoux E, Daniel MT, Taksin AL, Rousselot P, Sigaux F, Degos L, Altieri DC, Dombret H. Expression and prognostic significance of survivin in de novo acute leukemia. Br J Haematol. 2000; 111: 196–203. [DOI] [PubMed] [Google Scholar]
  • 35. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998; 396: 580–4. [DOI] [PubMed] [Google Scholar]
  • 36. Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, Pilotti S, Zunino F, Daidone MG. Expression of the anti‐apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci. 2002; 59: 1406–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. O'Connor DS, Wall NR, Porter AC, Altieri DC. A p34 (cdc2) survival checkpoint in cancer. Cancer Cell 2002; 2: 43–54. [DOI] [PubMed] [Google Scholar]
  • 38. Ling X, Bernacki RJ, Brattain MG, Li F. Induction of survivin expression by taxol (paclitxel) is an early event, which is independent of taxol‐mediated G2/M arrest. J Biol Chem 2004; 279: 15196–203. [DOI] [PubMed] [Google Scholar]
  • 39. Asanuma K, Moriai R, Yajima T, Yagihashi A, Yamada M, Kobayashi D, Watnabe N. Survivin as a radio‐resistance factor in pancreatic cancer. Jap J Cancer Res. 2000; 91: 1204–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Zhang M, Latham DE, Delaney MA, Chakravarti A. Survivin mediates resistance to antiandrogen therapy in prostate cancer. Oncogene. 2005. [DOI] [PubMed]
  • 41. Reed JC. The survivin saga goes in vivo . J Clin Invest. 2001; 108: 965–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003; 3: 46–54. [DOI] [PubMed] [Google Scholar]
  • 43. Grossman D, McNiff J.. Li F, Altieri D.. Expression and targetting of the apoptosis inhibitor, survivin, in human melanoma. J Inves Dermatol. 1999; 113: 1076–81. [DOI] [PubMed] [Google Scholar]
  • 44. Olie RA, Simões‐Wüst AP, Baumann B, Leech SH, Fabbro D, Stahel RA, Zangemeister‐Wittke U. A novel antisense oligonucleotide targeting survivin expression induces apoptotsis and sensitizes lung cancer cells to chemotherapy. Cancer Res. 2000; 60: 2805–9. [PubMed] [Google Scholar]
  • 45. Shanker SL, Mani S, O'Guin KN, Kandimalla ER, AgrawaL S, Shafit‐Zagardo B. Survivin inhibition induces human neural tumor cell death through caspase‐independent and ‐dependent pathways. J Neurochem. 2001; 79: 426–36. [DOI] [PubMed] [Google Scholar]
  • 46. Xia C, Xu Z, Yuan X, Uematsu K, You L, Li K, Li L, McCormick F, Jablons DM. Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides. Mol Cancer Ther. 2002; 1: 687–94. [PubMed] [Google Scholar]
  • 47. Lu B Mu Y, Cao C, Zeng F, Schneider S, Tan J, Price J, Chen J, Freeman M, Hallahan DE. Survivin as a therapeutic targer for radiation sensitization in lung cancer. Cancer Res. 2004; 64: 2840–5. [DOI] [PubMed] [Google Scholar]
  • 48. Kanwar JR, Shen W‐P, Kanwar RK, Berg RW, Krissansen GW. Effects of survivin antagonists on growth of established tumors and B7‐1 immunogene therapy. J Nat Cancer Inst. 2001; 93: 1541–52. [DOI] [PubMed] [Google Scholar]
  • 49. Sun LQ, Cairns MJ, Sarvaolac EG, Baker A, Gerlach WL. Catalytic nucleic acids: from lab to applications. Pharmacol Rev. 2000; 52: 325–47. [PubMed] [Google Scholar]
  • 50. Pennati M, Colella G, Folini M, Citti L, Daidone MG, Zaffaroni N. Ribozyme‐mediated attenuation of survivin expression sensitizes human melanoma cells to cisplatin‐induced apoptosis. J Clin Invest. 2002; 109: 285–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Pennati M, Binda M, de Cesare M, Pratesi G, Folini M, Citti L, Diadone MG, Zunino F, Zaffaroni N. Ribozyome‐mediated down‐regulation of survivin expression sensistizes human melanoma cells to topotecan in vitro and in vivo. Carcinogenesis. 2004; 25: 1129–36. [DOI] [PubMed] [Google Scholar]
  • 52. Pennati M, Binda M, Colella G, Folini M, Citti L, Villa R, Diadone MG, Zaffaroni N. Radiosensitization of human melanoma cells by ribozyme‐mediated inhibition of survivin expresson. J Invest Dermatol. 2003: 120; 648–54. [DOI] [PubMed] [Google Scholar]
  • 53. Pennati M, Binda M, Colella G, Zoppe' M, Folini M, Vignati S, Valentini A, Citti L, de Cesare M, Pratesi G, Gicca M, Diadone MG, Zaffaroni N. Ribozyme‐mediated inhibition of survivin expression increases spontaneous and drug‐induced apoptosis and decreases the tumorigenic potential of huma prostate cancer cells. Oncogene 2004; 23: 386–94. [DOI] [PubMed] [Google Scholar]
  • 54. Choi KS, Lee TH, Jung MH. Ribozyme‐mediated cleavage of the human survivin mRNA and inhibition of antiapoptotic function of survivin in MCF‐7 cells. Cancer Gene Ther. 2003; 10: 87–95. [DOI] [PubMed] [Google Scholar]
  • 55. Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther. 2005; 12: 217–27. [DOI] [PubMed] [Google Scholar]
  • 56. Kappler M, Bache M, Bartel F, Kotzsch M, Panian M, Wurl P, Blumke K, Schmidt H, Meye A, Taubert H. Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53. Cancer Gene Ther. 2004; 11: 186–93. [DOI] [PubMed] [Google Scholar]
  • 57. Kappler M, Taubert H, Bartel F, Blumke K, Panian M, Schmidt H, Dunst J, Bache M. Radiosensitization, after a combined treatment of survivin siRNA and irradiation, is correlated with the activation of caspases 3 and 7 in a wt‐p53 sarcoma cellline, but not in amt‐p53 sarcoma cell line. Oncol Rep. 2005; 13: 167–72. [PubMed] [Google Scholar]
  • 58. Chawal‐Sarker M, Bae SI, Reu FJ, Jacobs BS, Lindner DJ, Borden EC. Downregulation of Bcl‐2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL‐induces apoptosis. Cell Death Differ. 2004; 11: 915–23. [DOI] [PubMed] [Google Scholar]
  • 59. Coma S, Noe V, Lavarino C, Adan J, Rivas M, Lopez‐Matas M, Pagam R. Mitjans F, Vilaro S, Piulats J, Ciudad CJ. Use of siRNAs to inhibit steps leading to tumor angiogenesis. Oligonucleotides 2004; 14: 100–13. [DOI] [PubMed] [Google Scholar]
  • 60. Lee NS, Bertrand E, Rossi J. mRNA localization signals can enhance the intracellular effectiveness of hammerhead ribozymes. RNA. 1999; 5: 1200–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Scherer LJ, Rossi JJ. Approaches for the sequence‐specific knock‐down of mRNA. Nat Biotechnol. 2003; 21 1457–65. [DOI] [PubMed] [Google Scholar]
  • 62. Tu SP, Cui JT, Liston P, Huajiang X, Xu R, Lin MC, Zhu YB, Zou B, Ng SS, Jiang SH, Xia HH, Wong WM, Chan AO, Yuen MF, Lam SK, Kung HF, Wong BC. Gene therapy for colon cancer by adeno‐associated viral vector‐mediated transfer of survivin Cys84Ala mutant. Gastroenterology 2005; 128: 361–75. [DOI] [PubMed] [Google Scholar]
  • 63. Grossman D, Kim PJ, Schechner JS, Altieri DC. Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc Natl Acad Sci USA. 2001; 98: 635–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Mesri M, Wall NR, Li J, Kim RW, Altieri DC. Cancer gene therapy using a survivin mutant adneovirus. J Clin Invest. 2001; 108: 981–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. O'Connor DS, Wall NR, Porter AC, Altieri DC. A p34(cdc2) survival checkpoint in cancer. Cancer Cell.. 2004; 2: 43–54. [DOI] [PubMed] [Google Scholar]
  • 66. Wall NR, O'Connor DS, Plescia J, Pommier Y, Altieri DC. Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res. 2003; 63: 230–5. [PubMed] [Google Scholar]
  • 67. Nicholoson DW. From bench to clinic with apoptosis‐based therapeutic agents. Nature 2000; 407: 810–6. [DOI] [PubMed] [Google Scholar]
  • 68. Mesri M, Morales‐Ruiz M, Ackermann EJ, Bennett CF, Pober JS, Sessa WC, Altieri DC. Suppression of vascular endothelial growth factor‐mediated endothelial cell protection by survivin targeting. Am J Pathol. 2001; 158: 1757–65. [DOI] [PMC free article] [PubMed] [Google Scholar]

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