Advertisement

Journal of Molecular Medicine

, Volume 93, Issue 5, pp 559–572 | Cite as

Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma

  • Cindrilla Chumduri
  • Bernhard Gillissen
  • Anja Richter
  • Antje Richter
  • Ana Milojkovic
  • Tim Overkamp
  • Anja Müller
  • Christiane Pott
  • Peter T. DanielEmail author
Original Article

Abstract

Resistance to cell death is the major cause of chemotherapy failure in most kinds of cancers, including Burkitt lymphoma (BL). When analyzing therapy resistance in Burkitt lymphoma (BL), we discovered a link between apoptosis resistance and ploidy control. We therefore studied systematically a panel of 15 BL lines for apoptosis induction upon treatment with microtubule inhibitors and compared three types of microtubule toxins, i.e., paclitaxel, nocodazole and vincristine. We found an inverse relationship between apoptosis sensitivity and ploidy control. Thus, cells resistant to paclitaxel- or nocodazole-induced apoptosis underwent mitotic catastrophe and developed polyploidy (>4N). Mechanistically, apoptosis resistance was linked to failure of caspase activation, which was most pronounced in cells lacking the pro-apoptotic multidomain Bcl-2 homologs Bax and Bak. Pharmacological caspase inhibition promoted polyploidy upon exposure to paclitaxel and nocodazole supporting the relationship between resistance to apoptosis and polyploidization. Of note, vincristine induced persistent mitotic arrest but no loss of ploidy control. Considering targets to facilitate Bax/Bak-independent cell death and to avoid drug-induced mitotic catastrophe and consecutive mitotic catastrophe should be of great importance to overcome therapy resistance and therapy-related events that result in ploidy changes and tumor progression.

Key message

  • Inverse relation of apoptosis and polyploidy induction by paclitaxel or nocodazole in BL.

  • Resistant cells undergo mitotic catastrophe and develop polyploidy.

  • Lack of Bax/Bak confers resistance and leads to induction of polyploidy in BL.

  • Intact apoptosis response protects from polyploidy as a result of mitotic catastrophe.

Keywords

Mitotic catastrophe Aneuploidy Apoptosis Bax Bak Caspase 

Notes

Acknowledgments

This work was supported by grants from the Deutsche José Carreras Leukämiestiftung e.V. to P.T.D. and the Deutsche Krebshilfe-funded MMML (molecular mechanisms in malignant lymphoma) consortium to C.P. and P.T.D. We would like to thank Dr. Georg Bornkamm, Institute of Clinical Molecular Biology and Tumor Genetics, German Research Center for Environmental Health, München, Germany, and Dr. Marina Gutierrez, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia, for the kind gift of Burkitt lymphoma cell lines and Dr. Paul Ekert, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Australia, for providing us with murine FDM cells of various genetic backgrounds.

Conflict of interest

All authors have read and approved the final version of the manuscript. None of the authors has any type of financial interest to disclose.

Supplementary material

109_2014_1242_MOESM1_ESM.pdf (523 kb)
ESM 1 (PDF 522 kb)

References

  1. 1.
    Bornkamm GW (2009) Epstein-Barr virus and its role in the pathogenesis of Burkitt's lymphoma: an unresolved issue. Sem Can Biol 19:351–365CrossRefGoogle Scholar
  2. 2.
    Polack A, Hortnagel K, Pajic A, Christoph B, Baier B, Falk M, Mautner J, Geltinger C, Bornkamm GW, Kempkes B (1996) c-myc activation renders proliferation of Epstein-Barr virus (EBV)-transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. PNAS 93:10411–10416CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Prochownik EV (2008) c-Myc: linking transformation and genomic instability. Curr Mol Med 8:446–458CrossRefPubMedGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefPubMedGoogle Scholar
  5. 5.
    von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B, Daniel PT (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21:4009–4019CrossRefGoogle Scholar
  6. 6.
    Gillissen B, Essmann F, Graupner V, Starck L, Radetzki S, Dorken B, Schulze-Osthoff K, Daniel PT (2003) Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway. EMBO J 22:3580–3590CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Gillissen B, Essmann F, Hemmati PG, Richter A, Richter A, Oztop I, Chinnadurai G, Dorken B, Daniel PT (2007) Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis. J Cell Biol 179:701–715CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Graupner V, Alexander E, Overkamp T, Rothfuss O, De Laurenzi V, Gillissen BF, Daniel PT, Schulze-Osthoff K, Essmann F (2012) Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level. Cell Death Differ 18:1130–1139CrossRefGoogle Scholar
  9. 9.
    Daniel PT, Pun KT, Ritschel S, Sturm I, Holler J, Dorken B, Brown R (1999) Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice. Blood 94:1100–1107PubMedGoogle Scholar
  10. 10.
    Zaltsman Y, Shachnai L, Yivgi-Ohana N, Schwarz M, Maryanovich M, Houtkooper RH, Vaz FM, De Leonardis F, Fiermonte G, Palmieri F et al (2010) MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat Cell Biol 12:553–562CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Krammer PH, Kaminski M, Kiessling M, Gulow K (2007) No life without death. Adv Can Res 97:111–138CrossRefGoogle Scholar
  12. 12.
    Muer A, Overkamp T, Gillissen B, Richter A, Pretzsch T, Milojkovic A, Dorken B, Daniel PT, Hemmati P (2012) p14(ARF)-induced apoptosis in p53 protein-deficient cells is mediated by BH3-only protein-independent derepression of Bak protein through down-regulation of Mcl-1 and Bcl-xL proteins. J Biol Chem 287:17343–17352CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Strasser A, Cory S, Adams JM (2011) Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. EMBO J 30:3667–3683CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Doucet JP, Hussain A, Al-Rasheed M, Gaidano G, Gutierrez MI, Magrath I, Bhatia K (2004) Differences in the expression of apoptotic proteins in Burkitt's lymphoma cell lines: potential models for screening apoptosis-inducing agents. Leuk Lymphoma 45:357–362CrossRefPubMedGoogle Scholar
  15. 15.
    Fan S, el-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ Jr, Magrath I, Kohn KW, O'Connor PM (1994) p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res 54:5824–5830PubMedGoogle Scholar
  16. 16.
    Gutierrez MI, Cherney B, Hussain A, Mostowski H, Tosato G, Magrath I, Bhatia K (1999) Bax is frequently compromised in Burkitt's lymphomas with irreversible resistance to Fas-induced apoptosis. Cancer Res 59:696–703PubMedGoogle Scholar
  17. 17.
    McIntosh JR (1984) Cell biology. Microtubule catastrophe. Nature 312:196–197CrossRefPubMedGoogle Scholar
  18. 18.
    Portugal J, Bataller M, Mansilla S (2009) Cell death pathways in response to antitumor therapy. Tumori 95:409–421PubMedGoogle Scholar
  19. 19.
    Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:2825–2837CrossRefPubMedGoogle Scholar
  20. 20.
    Shay JW, Wright WE (2005) Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26:867–874CrossRefPubMedGoogle Scholar
  21. 21.
    Erenpreisa J, Kalejs M, Cragg MS (2005) Mitotic catastrophe and endomitosis in tumour cells: an evolutionary key to a molecular solution. Cell Biol Int 29:1012–1018CrossRefPubMedGoogle Scholar
  22. 22.
    Bhonde MR, Hanski ML, Budczies J, Cao M, Gillissen B, Moorthy D, Simonetta F, Scherubl H, Truss M, Hagemeier C et al (2006) DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53MUT cells contributes to apoptosis. J Biol Chem 281:8675–8685CrossRefPubMedGoogle Scholar
  23. 23.
    Bhonde MR, Hanski ML, Notter M, Gillissen BF, Daniel PT, Zeitz M, Hanski C (2006) Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth. Oncogene 25:165–175PubMedGoogle Scholar
  24. 24.
    Hemmati PG, Normand G, Gillissen B, Wendt J, Dorken B, Daniel PT (2008) Cooperative effect of p21Cip1/WAF-1 and 14-3-3sigma on cell cycle arrest and apoptosis induction by p14ARF. Oncogene 27:6707–6719CrossRefPubMedGoogle Scholar
  25. 25.
    Hemmati PG, Normand G, Verdoodt B, von Haefen C, Hasenjager A, Guner D, Wendt J, Dorken B, Daniel PT (2005) Loss of p21 disrupts p14 ARF-induced G1 cell cycle arrest but augments p14 ARF-induced apoptosis in human carcinoma cells. Oncogene 24:4114–4128CrossRefPubMedGoogle Scholar
  26. 26.
    Normand G, Hemmati PG, Verdoodt B, von Haefen C, Wendt J, Guner D, May E, Dorken B, Daniel PT (2005) p14ARF induces G2 cell cycle arrest in p53- and p21-deficient cells by down-regulating p34cdc2 kinase activity. J Biol Chem 280:7118–7130CrossRefPubMedGoogle Scholar
  27. 27.
    Linch DC (2012) Burkitt lymphoma in adults. Br J Haematol 156:693–703CrossRefPubMedGoogle Scholar
  28. 28.
    Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R, Dorken B, Daniel PT (2001) Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3. Blood 97:1378–1387CrossRefPubMedGoogle Scholar
  29. 29.
    Jabbour AM, Daunt CP, Green BD, Vogel S, Gordon L, Lee RS, Silke N, Pearson RB, Vandenberg CJ, Kelly PN et al (2010) Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. Blood 115:344–352CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    von Haefen C, Wieder T, Essmann F, Schulze-Osthoff K, Dorken B, Daniel PT (2003) Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop. Oncogene 22:2236–2247CrossRefGoogle Scholar
  31. 31.
    Ferry JA (2006) Burkitt's lymphoma: clinicopathologic features and differential diagnosis. Oncologist 11:375–383CrossRefPubMedGoogle Scholar
  32. 32.
    Castedo M, Coquelle A, Vivet S, Vitale I, Kauffmann A, Dessen P, Pequignot MO, Casares N, Valent A, Mouhamad S et al (2006) Apoptosis regulation in tetraploid cancer cells. EMBO J 25:2584–2595CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Davis FM, Tsao TY, Fowler SK, Rao PN (1983) Monoclonal antibodies to mitotic cells. PNAS 80:2926–2930CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Kelly GL, Strasser A (2011) The essential role of evasion from cell death in cancer. Adv Cancer Res 111:39–96CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Morizane Y, Honda R, Fukami K, Yasuda H (2005) X-linked inhibitor of apoptosis functions as ubiquitin ligase toward mature caspase-9 and cytosolic Smac/DIABLO. J Biochem 137:125–132CrossRefPubMedGoogle Scholar
  36. 36.
    Hecht JL, Aster JC (2000) Molecular biology of Burkitt's lymphoma. J Clin Oncol 18:3707–3721PubMedGoogle Scholar
  37. 37.
    Perkins AS, Friedberg JW (2008) Burkitt lymphoma in adults. Am Soc Hematol Educ Program :341-348Google Scholar
  38. 38.
    Farrell PJ, Allan GJ, Shanahan F, Vousden KH, Crook T (1991) p53 is frequently mutated in Burkitt's lymphoma cell lines. EMBO J 10:2879–2887PubMedCentralPubMedGoogle Scholar
  39. 39.
    Gidding CE, Kellie SJ, Kamps WA, de Graaf SS (1999) Vincristine revisited. Crit Rev Oncol Hematol 29:267–287CrossRefPubMedGoogle Scholar
  40. 40.
    King KL, Cidlowski JA (1995) Cell cycle and apoptosis: common pathways to life and death. J Cell Biochem 58:175–180CrossRefPubMedGoogle Scholar
  41. 41.
    Miranda EI, Santana C, Rojas E, Hernandez S, Ostrosky-Wegman P, Garcia-Carranca A (1996) Induced mitotic death of HeLa cells by abnormal expression of c-H-ras. Mutat Res 349:173–182CrossRefPubMedGoogle Scholar
  42. 42.
    Erenpreisa J, Kalejs M, Ianzini F, Kosmacek EA, Mackey MA, Emzinsh D, Cragg MS, Ivanov A, Illidge TM (2005) Segregation of genomes in polyploid tumour cells following mitotic catastrophe. Cell Biol Int 29:1005–1011CrossRefPubMedGoogle Scholar
  43. 43.
    Eriksson D, Blomberg J, Lindgren T, Lofroth PO, Johansson L, Riklund K, Stigbrand T (2008) Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells. Cancer Biother Radiopharm 23:541–549CrossRefPubMedGoogle Scholar
  44. 44.
    Wade M, Allday MJ (2000) Epstein-Barr virus suppresses a G(2)/M checkpoint activated by genotoxins. Mol Cell Biol 20:1344–1360CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Jazirehi AR, Bonavida B (2004) Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. Mol Cancer Ther 3:71–84CrossRefPubMedGoogle Scholar
  46. 46.
    Ibrado AM, Liu L, Bhalla K (1997) Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells. Cancer Res 57:1109–1115PubMedGoogle Scholar
  47. 47.
    Chu R, Terrano DT, Chambers TC (2012) Cdk1/cyclin B plays a key role in mitotic arrest-induced apoptosis by phosphorylation of Mcl-1, promoting its degradation and freeing Bak from sequestration. Biochem Pharmacol 83(2):199–206CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Harley ME, Allan LA, Sanderson HS, Clarke PR (2010) Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J 29(14):2407–2420CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Cindrilla Chumduri
    • 3
  • Bernhard Gillissen
    • 1
    • 2
  • Anja Richter
    • 1
    • 2
  • Antje Richter
    • 1
  • Ana Milojkovic
    • 3
  • Tim Overkamp
    • 1
  • Anja Müller
    • 1
  • Christiane Pott
    • 4
  • Peter T. Daniel
    • 1
    • 2
    • 3
    Email author
  1. 1.Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Virchow KlinikumHumboldt UniversityBerlinGermany
  2. 2.German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Clinical and Molecular OncologyUniversity Medical Center Charité and Max-Delbrück-Center for Molecular MedicineBerlin-BuchGermany
  4. 4.Department of Internal Medicine II, University Hospital Schleswig-HolsteinChristian-Albrechts UniversityKielGermany

Personalised recommendations