Inhibitors of Apoptosis Proteins (IAPs): Clinical Significance in Cancer Treatment Research
DOI:
https://doi.org/10.6000/1929-2279.2012.01.02.7Keywords:
Apoptosis, Survivin, X-linked inhibitor of apoptosis protein (XIAP), cellular IAPs, NAIP, ILP-2, Livin, BRUCE.Abstract
Apoptosis is a process, which involves a sequence of cellular changes, which ultimately lead to cell death. This programmed cell death is a normal phenomenon required for growth of an organism. Inhibition of apoptosis can result in a number of cancers, inflammatory and autoimmune diseases and viral infections. Inhibitors of apoptosis proteins (IAPs) are a family of structurally and functionally related proteins, which play a crucial role in apoptosis (programmed cell death), proliferation and angiogenesis. Till date 8 IAPs have been identified (Survivin, XIAP, Livin, cellular IAP 1 and 2, ILP-2, NAIP and BRUCE/Apollon). The current review discusses individual protein in details with respect to its structural features, functions and clinical significance. These proteins; especially survivin, XIAP and Livin have been found to express in wide range of malignancies and hence taken as a target of interest by various research groups. The review also highlights the various Phase- 1 and 2 studies of new therapeutic agents that are being developed either as a monotherapy or in combination with existent drugs, which target these IAPs.
References
Keith A, Alexander J, Julian L, Martin R, Walter R. In Apoptosis: Programmed Cell Death Eliminates Unwanted Cells. Molecular Biology of the Cell. 5th ed. Garland Science 2008; p. 1115.
Fulda S, Debatin KM. Targeting Inhibitor of Apoptosis Proteins (IAPs) for Diagnosis and Treatment of Human Diseases. Recent Patents on Anti-Cancer Drug Discovery 2006; 1: 81-9. http://dx.doi.org/10.2174/157489206775246539
Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770-6. http://dx.doi.org/10.1038/35037710
Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis 2000; 21: 485-95. http://dx.doi.org/10.1093/carcin/21.3.485
Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002; 2: 420-30. http://dx.doi.org/10.1038/nrc821
Naismith JH, Sprang SR. Modularity in the TNF-receptor family. Trends Biochem Sci 1998; 23: 74-9. http://dx.doi.org/10.1016/S0968-0004(97)01164-X
Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa, F. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 1999; 264: 687-701. http://dx.doi.org/10.1046/j.1432-1327.1999.00725.x
Loeffler M, Kroemer G. The mitochondrion in cell death control: certainties and incognita. Exp Cell Res 2000; 256: 19-26. http://dx.doi.org/10.1006/excr.2000.4833
Fadeel B, Orrenius S, Zhivotovsky B. Apoptosis in human disease: a new skin for the old ceremony? Biochem Biophys Res Commun 1999; 266: 699-17. http://dx.doi.org/10.1006/bbrc.1999.1888
Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov 2002; 1: 111-21. http://dx.doi.org/10.1038/nrd726
Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108: 153-64. http://dx.doi.org/10.1016/S0092-8674(02)00625-6
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70. http://dx.doi.org/10.1016/S0092-8674(00)81683-9
Wang XW. Role of p53 and apoptosis in carcinogenesis. Anticancer Res 1999; 19: 4759-71.
Takahashi R, Deveraux Q, Tamm I, Welsh K, Assa-Munt N, Salvesen GS, et al. A single BIR domain of XIAP sufficient for inhibiting caspases. J Biol Chem 1998; 273: 7787-90. http://dx.doi.org/10.1074/jbc.273.14.7787
Nachmias B, Ashhab Y, Ben-Yehuda D. The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 2004; 14: 231-43. http://dx.doi.org/10.1016/j.semcancer.2004.04.002
Salvesen GS, Duckett, CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002; 36: 401-10. http://dx.doi.org/10.1038/nrm830
Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G et.al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 1996; 379: 349-53. http://dx.doi.org/10.1038/379349a0
Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J 1996; 15: 2685-94.
Holcik M, Korneluk RG. Functional Characterization of the X-Linked Inhibitor of Apoptosis (XIAP) Internal Ribosome Entry Site Element: Role of La Autoantigen in XIAP Translation. Mol Cell Biol 2000; 20: 4648-57. http://dx.doi.org/10.1128/MCB.20.13.4648-4657.2000
Deveraux QL, Reed JC. IAP family proteins - suppressors of apoptosis. Genes Dev 1999; 13: 239-52. http://dx.doi.org/10.1101/gad.13.3.239
Duckett CS, Li F, Wang Y, Tomaselli KJ, Thompson CB, Armstrong RC. Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c. Mol Cell Biol 1998; 18: 608-15.
Eckelman BP, Salvesen GS, Scott, FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 2006; 7: 988-94. http://dx.doi.org/10.1038/sj.embor.7400795
Plesner A, Liston P, Tan R, Robert G, Korneluk C, Verchere B. The X-Linked Inhibitor of Apoptosis Protein Enhances Survival of Murine Islet Allografts. Diabetes 2005; 54: 2533-40. http://dx.doi.org/10.2337/diabetes.54.9.2533
Watson RW, Fitzpatrick JM. Targeting apoptosis in prostate cancer: focus on caspases and inhibitors of apoptosis proteins. BJU Int 2005; 96: 30-4. http://dx.doi.org/10.1111/j.1464-410X.2005.05944.x
Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B, et al. Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 2011; 13: 255-62. http://dx.doi.org/10.1097/GIM.0b013e3182088158
Burstein E, Lakshmanan G, Robert DD, Bart VDS, John CW, Leo WJK, et al. A novel role for XIAP in copper homeostasis through regulation of MURR1. EMBO J 2004; 23: 244-54. http://dx.doi.org/10.1038/sj.emboj.7600031
Puig S, Thiele DJ. Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 2002; 6: 171-80. http://dx.doi.org/10.1016/S1367-5931(02)00298-3
Tao TY, Liu F, Klomp L, Wijmenga C, Gitlin JD. The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein. J Biol Chem 2003; 278: 41593-6. http://dx.doi.org/10.1074/jbc.C300391200
Hridayesh P, Marco A, Daniel B, Tanja K, Thomas R. Deficiency of XIAP Leads to Sensitization for Chlamydophila pneumoniae Pulmonary Infection and Dysregulation of Innate Immune Response in Mice. J Biol Chem 2010; 285: 20291-302. http://dx.doi.org/10.1074/jbc.M109.096297
Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WH, et al. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J Bio Chem 2002; 277: 12275-9. http://dx.doi.org/10.1074/jbc.M112045200
Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 2000; 10: 1359-66. http://dx.doi.org/10.1016/S0960-9822(00)00781-8
Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H, et al. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J 2005; 385: 11-20. http://dx.doi.org/10.1042/BJ20041108
Colnaghi, R, Connell CM, Barrett RM, Wheatley SP. Separating the anti-apoptotic and mitotic roles of survivin. J Biol Chem 2006; 281: 33450-6. http://dx.doi.org/10.1074/jbc.C600164200
O'Driscoll L, Linehan R, Clynes M. Survivin: role in normal cells and in pathological conditions. Curr Cancer Drug Targets 2003; 3: 131-52. http://dx.doi.org/10.2174/1568009033482038
Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 38: 917-21. http://dx.doi.org/10.1038/nm0897-917
Verdecia MA, Huang H, Dutil E, Kaiser DA, Hunter T, Noel JP. Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement. Nat Struct Biol 2000; 77: 602-8.
Chantalat L, Skoufias DA, Kleman JP, Jung B, Dideberg O, Margolis RL. Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Mol Cell 2000; 61: 183-9.
Kobayashi K, Hatano M, Otaki M, Ogasawara T, Tokuhisa T. Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci USA 1999; 964: 1457-62. http://dx.doi.org/10.1073/pnas.96.4.1457
O’Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A et.al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA 2000; 9724: 13103-7. http://dx.doi.org/10.1073/pnas.240390697
Dohi T, Beltrami E, Wall NR, Plescia J, Altieri DC. Mitochondrial surviving inhibits apoptosis and promotes tumorigenesis. J Clin Invest 2004; 1148: 1117-27.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 1021: 43-53. http://dx.doi.org/10.1016/S0092-8674(00)00009-X
Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 1021: 33-42. http://dx.doi.org/10.1016/S0092-8674(00)00008-8
Chiou SK, Jones MK, Tarnawski AS. Survivin - an anti-apoptosis protein: its biological roles and implications for cancer and beyond. Med Sci Monit 2003; 9: 25-9.
Ramesh H, Srinivasa MS, Pinaki D, Muniswamy M, Richard W, ZhiJia Z, et al. The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein. J Biol Chem 2003; 278: 38699-706. http://dx.doi.org/10.1074/jbc.M303179200
Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Lisa CM, et al. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 2002; 277: 445-54. http://dx.doi.org/10.1074/jbc.M109891200
Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J 1997; 16: 6914-25. http://dx.doi.org/10.1093/emboj/16.23.6914
Shu HB, Takeuchi M, Goeddel DV. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci USA 1996; 93: 13973-8. http://dx.doi.org/10.1073/pnas.93.24.13973
Li X, Yang Y, Ashwell JD. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 2002; 416(6878): 345-7. http://dx.doi.org/10.1038/416345a
Thome M, Hofmann K, Burns K, Martinon F, Bodmer JL, Mattmann C, et al. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr Biol 1998; 8: 885-8. http://dx.doi.org/10.1016/S0960-9822(07)00352-1
Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci USA 1996; 93: 4974-8. http://dx.doi.org/10.1073/pnas.93.10.4974
Yoneda T, Imaizumi K, Maeda M, Yui D, Manabe T, Katayama T, et al. Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein. J Biol Chem 2000; 275: 11114-20. http://dx.doi.org/10.1074/jbc.275.15.11114
Bertrand JM, Milutinovic S, Dickson KM, Chi HW, Boudreault A, Durkin J, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 2008; 30: 689-700. http://dx.doi.org/10.1016/j.molcel.2008.05.014
Sekine K, Takubo K, Kikuchi R, Nishimoto M, Kitagawa M, Fuminori A, et al. Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J Biol Chem 2008; 283: 8961-8. http://dx.doi.org/10.1074/jbc.M709525200
Mace PD, Linke K, Feltham R, Schumacher FR, Smith CA, Vaux DL, et al. Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment. J Biol Chem 2008; 283: 31633-40. http://dx.doi.org/10.1074/jbc.M804753200
Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. Immunity 1998; 8: 297-303. http://dx.doi.org/10.1016/S1074-7613(00)80535-X
Lee TH, Shank J, Cusson N, Kelliher MA. J Biol Chem 2004; 279: 33185-91. http://dx.doi.org/10.1074/jbc.M404206200
Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 1995; 80: 167-78. http://dx.doi.org/10.1016/0092-8674(95)90461-1
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