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Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis

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Abstract

In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly, we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/DDP and A2780/ADR, providing evidence that: (i) the three cell lines are either scarcely sensitive (A2780 and A2780/ADR) or moderately sensitive (A2780/DDP) to the cytotoxic effects of TRAIL; (ii) the elevated c-FLIP expression observed in ovarian cancer cells is a major determinant of TRAIL resistance of these cells; (iii) proteasome inhibitors (PS-341 or MG132) are able to exert a significant pro-apoptotic effect and to greatly enhance the sensitivity of both chemosensitive and chemoresistant A2780 cells to TRAIL; (iv) proteasome inhibitors damage mitochondria through stabilization of BH3-only proteins, Bax and caspase activation and significantly enhance TRAIL-R2 expression; (v) TRAIL-R2, but not TRAIL-R1, mediates the apoptotic effects of TRAIL on ovarian cancer cells. Importantly, studies on primary ovarian cancer cells have shown that these cells are completely resistant to TRAIL and proteasome inhibitors markedly enhance the sensitivity of these cells to TRAIL. Given the high susceptibility of ovarian cancer cells to proteasome inhibitors, our results further support the experimental use of these compounds in the treatment of ovarian cancer.

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References

  1. Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351:2519–2529

    Article  PubMed  CAS  Google Scholar 

  2. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  PubMed  CAS  Google Scholar 

  3. Daniel NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:206–219

    Google Scholar 

  4. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  5. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885

    Article  PubMed  CAS  Google Scholar 

  6. Ashkenazi A (2002) Targeting death and decoy receptors of the tumor-necrosis factor superfamily. Nature Rev Cancer 2:420–431

    Article  CAS  Google Scholar 

  7. Bouralexis S, Findley DM (2005) Death to the dad guys: targeting cancer via Apo2L/TRAIL. Apoptosis 10:35–51

    Article  PubMed  CAS  Google Scholar 

  8. Kimberley FC, Screaton GR (2004) Following a TRAIL: update on a ligand and its five receptors. Cell Res 14:359–372

    Article  PubMed  CAS  Google Scholar 

  9. Horak P, Pils D, Haller G, Pribill I, Roessler M, Tomek S, Horvat R, Zeillinger R, Zielinski C, Krainer M (2005) Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer. Mol Cancer Res 3:335–343

    Article  PubMed  CAS  Google Scholar 

  10. Horak P, Pils D, Kaider A, Pinter A, Elandt K, Sax C, Zielinzki CC, Horvat R, Ziellinger R, Reinthaller A, Krainer M (2005) Perturbation of the tumor necrosis factor-related apoptosis-inducing ligand cascade in ovarian cancer: overexpression of FLIPL and deregulation of the functional receptors DR4 and DR5. Clin Cancer Res 11:8585–8591

    Article  PubMed  CAS  Google Scholar 

  11. Goldberg AL, Stein R, Adams J (1995) New insights into proteasome function: from archeobacteria to drug development. Chem Biol 2:503–508

    Article  PubMed  CAS  Google Scholar 

  12. Wong CY, Mayo MW, Baldwin AS (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science 274:784–787

    Article  Google Scholar 

  13. Lashinger LM, Zhu K, Williams SA, Shrader M, Dinney CPN, McConkey DJ (2005) Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells. Cancer Res 65:4902–4908

    Article  PubMed  CAS  Google Scholar 

  14. Frankel A, Man S, Elliott P, Adams J, Kerbel RS (2000) Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 6:3719–3728

    PubMed  CAS  Google Scholar 

  15. Zhu H, Zhang L, Dong F, Guo W, Wu S, Teraishi F, Davis JJ, Chiao PJ, Fang B (2005) Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene 24:4993–4999

    Article  PubMed  CAS  Google Scholar 

  16. Aghajanian C, Diron DS, Sabbatini P, Raizer JJ, Dupont J, Spriggs DR (2005) Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol 23:5943–5949

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Georgakis GV, Li Y, Humphreys R, Andreef M, O’Brien S, Younes M, Carbone A, Albert V, Younes A (2005) Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 130:501–510

    Article  PubMed  CAS  Google Scholar 

  19. Pukac L, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C, Riccobene T, Johnson R (2005) HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumor types in vitro and in vivo. Br J Cancer 92:1430–1441

    Article  PubMed  CAS  Google Scholar 

  20. Vikhanskaya F, Vignati S, Beccaglia P, Ottoboni C, Russo P, D’Incalci M, Broggini M (1998) Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclytaxol by inducing G2/M arrest and apoptosis. Exp Cell Res 241:96–101

    Article  PubMed  CAS  Google Scholar 

  21. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377

    Article  PubMed  CAS  Google Scholar 

  22. Yang X, Fraser M, Moll UM, Basak A, Tsang BK (2006) Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspases-dependent mitochondrial death pathway. Cancer Res 66:3126–3136

    Article  PubMed  CAS  Google Scholar 

  23. Ward MW, Rehm M, Duessmann H, Kacmar S, Concannon CG, Prehn JH (2006) Real time single cell analysis of Bid cleavage and Bid translocation during caspase-dependent and neuronal caspase-independent apoptosis. J Biol Chem 281:5837–5844

    Article  PubMed  CAS  Google Scholar 

  24. Willis SN, Adams JM (2005) Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17:617–625

    Article  PubMed  CAS  Google Scholar 

  25. Cuello M, Ettenberg SA, Nau MN, Lipkowitz S (2001) Synergistic induction of apoptosis by the combination of TRAIL and chemotherapy in chemoresistant ovarian cancer cells. Gynecol Oncol 81:380–390

    Article  PubMed  CAS  Google Scholar 

  26. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: release of cytochrome C from mitochondria blocked. Science 275:1129–1132

    Article  PubMed  CAS  Google Scholar 

  27. Lane D, Cartier A, L’Esperance S, Cote M, Rancourt C, Piche A (2004) Differential induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand in human ovarian carcinoma cells. Gynecol Oncol 93:594–604

    Article  PubMed  CAS  Google Scholar 

  28. Griffin D, Wittmann S, Guo F, Nimmanapalli R, Bali P, Wang HG, Bhalla K (2003) Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells. Gynecol Oncol 89:37–47

    Article  PubMed  CAS  Google Scholar 

  29. Tomek S, Horak P, Pribill I, Haller G, Rossler M, Zielinski CC, Pils D, Krainer M (2004) Resistance to TRAIL-induced apoptosis in ovarian cancer cell lines is overcome by co-treatment with cytotoxic drugs. Gynecol Oncol 94:107–114

    Article  PubMed  CAS  Google Scholar 

  30. Liu P, Mao H, Hou P (2006) Synergistic antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand combined with cisplatin in ovarian carcinoma cell lines in vitro and in vivo. Int J Gynecol Cancer 16:538–548

    Article  PubMed  CAS  Google Scholar 

  31. He Q, Huang Y, Sheikh MS (2004) Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and deficient cells. Oncogene 23:2554–2558

    Article  PubMed  CAS  Google Scholar 

  32. Kelley RF, Totpal K, Lindstrom SH, Mathieu M, Billeci K, Deforge L, Pai R, Hymowitz SG, Ashkenazi A (2005) Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signalling. J Biol Chem 280:2205–2212

    Article  PubMed  CAS  Google Scholar 

  33. Yoshida T, Shiraishi T, Nakata S, Horinaka M, Wakada M, Mizutani Y, Miki T, Sakai T (2005) Proteasome inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein. Cancer Res 65:5662–5667

    Article  PubMed  CAS  Google Scholar 

  34. Nencioni A, Wille L, Dal Bello G, Boy D, Cirmena G, Wesselborg S, Belka K, Brossard P, Patrone F, Ballestrero A (2005) Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells. Clin Cancer Res 11:4259–4265

    Article  PubMed  CAS  Google Scholar 

  35. Lang-Rollin I, Vekrellis K, Wang Q, Rideout HJ, Stefanis L (2006) Application of proteasomal inhibitors to mouse sympathetic neurons activates the intrinsic apoptotic pathway. J Neurochem 90:1511–1520

    Article  Google Scholar 

  36. Pasquini L, Petrucci E, Riccioni R, Petronelli A, Testa U (2006) Sensitivity and resistance of human cancer cells to TRAIL: mechanisms and therapeutical perspectives. Cancer Therapy 4:47–72

    Google Scholar 

  37. Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, et al (2002) PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Therapeutics 1:841–849

    CAS  Google Scholar 

  38. Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ (2003) Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein Bim. J Biol Chem 278:18811–18816

    Article  PubMed  CAS  Google Scholar 

  39. Tan TT, Degenhardt K, Nelson DA, Beudoin B, Nieves-Neira W, Bouillet P, Villunger A, Adams JM, White E (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238

    Article  PubMed  CAS  Google Scholar 

  40. Letai A, Bassik MC, Walensky LD, Sarcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving ac prototype cancer therapeutics. Cancer Cell 2:183–192

    Article  PubMed  CAS  Google Scholar 

  41. Zhu H, Zhang L, Dong F, Guo W, Wu S, Teraishi F, Davis JJ, Chiao PJ, Fang B (2005) Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene 24:4993–4999

    Article  PubMed  CAS  Google Scholar 

  42. Malti N, Johnson T, Puthalalath H, Coultas L, Adams J, Kraft AS (2005) The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther 4:443–449

    Google Scholar 

  43. Lauricella M, Emanuele S, D’Anneo A, Calvaruso G, Vassallo B, Carlisi D, Portanova P, Vento R, Tesoriere G (2006) JNK and AP-1 mediate apoptosis induced by bortezomib in HepG2 cells via FasL/caspase-8 and mitochondria-dependent pathways. Apoptosis 11:607–625

    Article  PubMed  CAS  Google Scholar 

  44. Hsu SY, Lin P, Hisueh AJW (1998) BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. Mol Endocrinol 12:1432–1440

    Article  PubMed  CAS  Google Scholar 

  45. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckweth TL, Dinges J, Hajduk PJ (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature 435:677–681

    Article  PubMed  CAS  Google Scholar 

  46. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Kormeyer S, Armstrong SA, Letai A (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365

    Article  PubMed  CAS  Google Scholar 

  47. Joazeiro C, Anderson KC, Hunter T (2006) Proteasome inhibitor drugs on the rise. Cancer Res 66:7840–7842

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical Oncology Section, Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Ernestina Saulle, Alessia Petronelli, Luca Pasquini, Eleonora Petrucci, Gualtiero Mariani, Mauro Biffoni, Cesare Peschle & Ugo Testa

  2. Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy

    Gianluigi Ferretti & Francesco Cognetti

  3. Department of Oncology, Catholic University, Campobasso, Italy

    Giovanni Scambia

  4. Institute of Gynecology, Perinatalogy and Child Health, University “La Sapienza” of Rome, Viale Regina Elena 324, 00161, Rome, Italy

    Pierluigi Benedetti-Panici

  5. Department of Oncology Research, Human genome sciences Inc., Rockville, MD, 20850, USA

    Robin Humphreys

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  1. Ernestina Saulle
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Correspondence to Ugo Testa.

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Saulle, E., Petronelli, A., Pasquini, L. et al. Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis. Apoptosis 12, 635–655 (2007). https://doi.org/10.1007/s10495-006-0025-9

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