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cIAP2 is highly expressed in Hodgkin–Reed–Sternberg cells and inhibits apoptosis by interfering with constitutively active caspase-3

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Abstract

In this study, the expression of activated caspase-3 by the tumor cells of classical Hodgkin lymphoma (cHL), the Hodgkin–Reed–Sternberg (HRS) cells, is confirmed. This raises the question why caspase-3 does not kill HRS cells. There are only a few molecules, which are able to directly inhibit caspase-3. One of them is cIAP2. We show that cIAP2 is expressed in the HRS cells in 20 of 23 cHL cases by in situ hybridization. Suppression experiments with cIAP2 antisense RNA show that down-regulation of cIAP2 significantly reduces apoptosis resistance in cHL cell lines. cIAP2 overexpression appears to be unique for HRS cells since the tumor cells of non-Hodgkin lymphomas are nearly cIAP2-negative. We demonstrate that cIAP2 is inducible by CD30 stimulation in cHL cell lines of T-cell origin and anaplastic large cell lymphoma cell lines, whereas cHL cell lines of B-cell origin constitutively express cIAP2. Inhibition of cIAP2 expression by cIAP2 antisense RNA decreases resistance to apoptosis. The results indicate that cIAP2 contributes to the apoptosis resistance of HRS cells, mainly by inhibiting effector caspases. According to these findings, a therapeutical application of inhibitors of apoptosis proteins antagonists in cHL appears promising.

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References

  1. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308

    Article  PubMed  CAS  Google Scholar 

  2. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312

    Article  PubMed  CAS  Google Scholar 

  3. Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6:287–297

    Article  PubMed  CAS  Google Scholar 

  4. Chhanabhai M, Krajewski S, Krajewska M, Wang HG, Reed JC, Gascoyne RD (1997) Immunohistochemical analysis of interleukin-1β-converting enzyme/Ced-3 family protease, CPP32/Yama/caspase-3, in Hodgkin’s disease. Blood 90:2451–2455

    PubMed  CAS  Google Scholar 

  5. Dukers DF, Meijer CJLM, ten Berge RL, Vos W, Ossenkoppele GJ, Oudejans JJ (2002) High numbers of active caspase-3-positive Reed–Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome. Blood 100:36–42

    Article  PubMed  CAS  Google Scholar 

  6. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt, Diehl V (1982) Production of a monoclonal antibody specific for Hodgkin and Sternberg–Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 299:65–67

    Article  PubMed  CAS  Google Scholar 

  7. Herbst H, Dallenbach F, Hummel M, Pileri S, Müller-Lantzsch N, Stein H (1991) Epstein–Barr virus latent membrane protein expression in Hodgkin and Reed–Sternberg cells. Proc Natl Acad Sci U S A 88:4766–4770

    Article  PubMed  CAS  Google Scholar 

  8. Carbone A, Gloghini A, Gattei V, Aldinucci D, Degan M, De Paoli P, Zagonel V, Pinto A (1995) Expression of functional CD40 antigen on Reed–Sternberg cells and Hodgkin’s disease cell lines. Blood 85:780–789

    PubMed  CAS  Google Scholar 

  9. Re D, Hofmann A, Wolf J, Diehl V, Staratschek-Jox A (2000) Cultivated H-RS cells are resistant to CD95L-mediated apoptosis despite expression of wild-type CD95. Exp Hematol 28:31–35

    Article  PubMed  CAS  Google Scholar 

  10. Maggio EM, Van Den Berg A, de Jong D, Diepstra A, Poppema S (2003) Low frequency of FAS mutations in Reed–Sternberg cells of Hodgkin’s lymphoma. Am J Pathol 162:29–35

    PubMed  CAS  Google Scholar 

  11. Thomas RT, Kallenborn A, Wickenhauser C, Schultze JL, Draube A, Vockerodt M, Re D, Diehl V, Wolf J (2002) Constitutive expression of c-FLIP in Hodgkin and Reed–Sternberg cells. Am J Pathol 160:1521–1528

    PubMed  CAS  Google Scholar 

  12. Mathas S, Lietz A, Anagnostopoulos I, Hummel F, Wiesner B, Janz M, Jundt F, Hirsch B, Jöhrens-Leder K, Vornlocher H-P, Bommert K, Stein H, Dörken B (2004) c-FLIP mediated resistance of Hodgkin/Reed–Sternberg cells to death receptor-induced apoptosis. J Exp Med 199:1041–1052

    Article  PubMed  CAS  Google Scholar 

  13. Dutton A, O’Neil JD, Milner AE, Reynolds GM, Starczynski J, Crocker J, Young LS, Murray PG (2004) Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin’s lymphoma cells from autonomous Fas-mediated death. Proc Natl Acad Sci U S A 101:6611–6616

    Article  PubMed  CAS  Google Scholar 

  14. Kashkar H, Haefs C, Shin H, Hamilton-Dutoit SJ, Salvesen GS, Krönke M, Jürgensmeister JM (2003) XIAP-mediated caspase inhibition in Hodgkin’s lymphoma-derived B cells. J Exp Med 198:341–347

    Article  PubMed  CAS  Google Scholar 

  15. Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P (1999) The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18) (q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93:3601–3609

    PubMed  CAS  Google Scholar 

  16. Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H, Ota H, Nakamura S, Morishima Y, Taniwaki M, Seto M (1999) A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18:5785–5794

    Article  PubMed  CAS  Google Scholar 

  17. Hinz M, Löser P, Mathas S, Krappmann D, Dörken B, Scheidereit C (2001) Constitutive NF-κB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed–Sternberg cells. Blood 97:2798–2807

    Article  PubMed  CAS  Google Scholar 

  18. Messineo C, Jamerson MH, Hunter E, Braziel R, Bagg A, Irving SG, Cossman J (1998) Gene expression by single Reed–Sternberg cells: pathways of apoptosis and activation. Blood 91:2443–2451

    PubMed  CAS  Google Scholar 

  19. Zheng B, Fiumara P, Li YV, Georgakis G, Snell V, Younes M, Vauthey JN, Carbone A, Younes A (2003) MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood 102:1019–1027

    Article  PubMed  CAS  Google Scholar 

  20. Schmelz K, Wieder T, Tamm I, Müller A, Essmann F, Geilen CC, Schulze-Osthoff K, Dörken B, Daniel PT (2004) Tumor necrosis factor alpha sensitizes malignant cells to chemotherapeutic drugs via the mitochondrial apoptosis pathway independently of caspase-8 and NF-κB. Oncogene 23:6743–6759

    Article  PubMed  CAS  Google Scholar 

  21. Muta H, Boise LH, Fang L, Podack ER (2000) CD30 signals integrate expression of cytotoxic effector molecules, lymphocyte trafficking signals, and signals for proliferation and apoptosis. J Immunol 165:5105–5111

    PubMed  CAS  Google Scholar 

  22. Jaffe ES, Harris NL, Stein H, Vardiman JM (eds) (2001) World Health Organization classification of tumours, pathology & genetics: tumours of haematopoietic and lymphoid tissues. IARC, Lyon

  23. Drexler HG (ed) (2001). The leukemia-lymphoma cell line facts book. Academic Press, San Diego

  24. Jat P, Arrand JR (1982) In vitro transcription of two Epstein–Barr virus specified small RNA molecules. Nucleic Acids Res 10:3407–3425

    Article  PubMed  CAS  Google Scholar 

  25. Cordell J, Falini B, Erber ON, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY (1984) Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 32:219–229

    PubMed  CAS  Google Scholar 

  26. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocytes apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139:271–279

    Article  PubMed  CAS  Google Scholar 

  27. Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (eds) (2005). In: Current protocols in molecular biology. Wiley, New York

  28. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  29. Dürkop H, Hirsch B, Hahn C, Foss HF, Stein H (2003) Differential expression and function of A20 and TRAF1 in Hodgkin lymphoma and anaplastic large cell lymphoma and their induction by CD30 stimulation. J Pathol 200:214–221

    Article  Google Scholar 

  30. Grell M, Zimmermann G, Gottfried E, Chen CM, Grünwald U, Huang DC, Lee YH, Dürkop H, Engelmann H, Scheurich P, Wajant H, Strasser A (1999) Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. EMBO J 18:3034–3043

    Article  PubMed  CAS  Google Scholar 

  31. Nonaka M, Horie R, Itoh K, Watanabe T, Yamamoto N, Yamaoka S (2005) Aberrant NF-κB2/p52 expression in Hodgkin/Reed–Sternberg cells and CD30-transformed rat fibroblasts. Oncogene 24:3976–86

    Article  PubMed  CAS  Google Scholar 

  32. Hübinger G, Schneider C, Stöhr D, Ruff H, Kirchner D, Schwänen C, Schmid M, Bergmann L, Müller E (2004) CD30-induced up-regulation of the inhibitor of apoptosis genes cIAP1 and cIAP2 in anaplastic large cell lymphoma cells. Exp Hematol 32:382–389

    Article  PubMed  Google Scholar 

  33. Hinz M, Lemke P, Anagnostopoulos I, Hacker C, Krappmann D, Mathas S, Dörken B, Zenke M, Stein H, Scheidereit C (2004) Nuclear factor κB-dependent gene expression profiling of Hodgkin’s disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 196:605–617

    Article  Google Scholar 

  34. Emmerich F, Meiser M, Hummel M, Demel G, Foss HD, Jundt F, Mathas S, Krappmann D, Scheidereit C, Stein H, Dörken B (1999) Overexpression of IκBα without inhibition of NF-κB activity and mutations in the IκBα gene in Reed–Sternberg cells. Blood 94:3129–3134

    PubMed  CAS  Google Scholar 

  35. Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT (1999) Mutations in the IκBα gene in Hodgkin’s disease suggest a tumour suppressor role for IκBα. Oncogene 18:3063–3070

    Article  PubMed  CAS  Google Scholar 

  36. Jungnickel B, Staratschek-Jox A, Bräuninger A, Spieker T, Wolf J, Diehl V, Hansmann ML, Rajewsky K, Küppers R (2000) Clonal deleterious mutations in the IκBα gene in the malignant cells in Hodgkin’s lymphoma. J Exp Med 191:395–402

    Article  PubMed  CAS  Google Scholar 

  37. Pinto A, Aldinucci D, Gloghini A, Zagonel V, Degan M, Perin V, Todesco M, De Iuliis A, Improta S, Sacco C, Gattei V, Gruss HJ, Carbone A (1997) The role of eosinophils in the pathobiology of Hodgkin’s disease. Ann Oncol 8(Suppl 2):89–96

    Article  PubMed  Google Scholar 

  38. Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanagae Y, Saito I, Higashihara M, Mori S, Kadin M, Watanabe T (2002) Ligand-independent signaling by overexpressed CD30 drives NF-κB activation in Hodgkin–Reed–Sternberg cells. Oncogene 21:2493–2503

    Article  PubMed  CAS  Google Scholar 

  39. Clodi K, Asgari Z, Younes M, Palmer JL, Cabanillas F, Carbone A, Andreeff M, Younes A (2002) Expression of CD40 ligand (CD154) in B and T lymphocytes of Hodgkin disease: potential therapeutic significance. Cancer 94:1–5

    Article  PubMed  CAS  Google Scholar 

  40. Metkar SS, Naresh KN, Redkar AA, Soman CS, Advani SH, Nadkarni JJ (1999) Expression of Fas and Fas ligand in Hodgkin’s disease. Leuk Lymphoma 33:521–530

    PubMed  CAS  Google Scholar 

  41. Krajewski S, Gascoyne RD, Zapata JM, Krajewska M, Kitada S, Chhanabhai M, Horsman D, Berean K, Piro LD, Fugier-Vivier I, Liu Y-J, Wang H-G, Reed JC (1997) Immunolocalization of the ICE/Ced-3-family protease, CPP32 (caspase-3) in non-Hodgkin’s lymphomas, chronic lymphocytic leukemias, and reactive lymph nodes. Blood 89: 3817-3825

    PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Prof. Dr. HD Foss who placed the in situ hybridization to our disposal. We are indebted to Mrs. E. Berg, N. Thiele, and E. von der Wall for the excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (SFB 366).

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  1. Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Horst Dürkop, Burkhard Hirsch, Corinna Hahn & Harald Stein

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  1. Horst Dürkop
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Correspondence to Horst Dürkop.

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Dürkop, H., Hirsch, B., Hahn, C. et al. cIAP2 is highly expressed in Hodgkin–Reed–Sternberg cells and inhibits apoptosis by interfering with constitutively active caspase-3. J Mol Med 84, 132–141 (2006). https://doi.org/10.1007/s00109-005-0003-7

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