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The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells

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Abstract

The proteasome inhibitors are a new class of antitumor agents. These inhibitors cause the accumulation of many proteins in the cell with the induction of apoptosis including TRAIL death receptors DR4 and DR5, but the role of the TRAIL apoptotic pathway in proteasome inhibitor cytotoxicity is unknown. Herein, we have demonstrated that the induction of apoptosis by the proteasome inhibitors, MG-132 and PS-341 (bortezomib, Velcade), in primary CLL cells and the Burkitt lymphoma cell line, BJAB, is associated with up-regulation of TRAIL and its death receptors, DR4 and DR5. In addition, FLICE-like inhibitory protein (c-FLIP) protein is decreased. MG-132 treatment increases binding of DR5 to the adaptor protein FADD, and causes caspase-8 activation and cleavage of pro-apoptotic BID. Moreover, DR4:Fc or blockage of DR4 and DR5 expression using RNA interference, which prevents TRAIL apoptotic signaling, blocks proteasome inhibitor induced apoptosis. MG-132 also increases apoptosis and DR5 expression in normal B-cells. However, when the proteasome inhibitors are combined with TRAIL or TRAIL receptor activating antibodies the amount of apoptosis is increased in CLL cells but not in normal B cells. Thus, activation of the TRAIL apoptotic pathway contributes to proteasome inhibitor induced apoptosis in CLL cells.

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References

  1. Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5(5):417–421

    Article  PubMed  CAS  Google Scholar 

  2. Almond JB, Cohen GM (2002) The proteasome: A novel target for cancer chemotherapy. Leukemia 16(4):433–443

    Article  PubMed  CAS  Google Scholar 

  3. Voorhees PM, Dees EC, O’Neil B, Orlowski RZ (2003) The proteasome as a target for cancer therapy. Clin Cancer Res 9(17):6316–6325

    PubMed  CAS  Google Scholar 

  4. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617

    Article  PubMed  CAS  Google Scholar 

  5. Dou QP, Goldfarb RH (2002) Bortezomib (millennium pharmaceuticals). IDrugs 5(8):828–834

    PubMed  CAS  Google Scholar 

  6. Naujokat C, Sezer O, Zinke H, Leclere A, Hauptmann S, Possinger K (2000) Proteasome inhibitors induced caspase-dependent apoptosis and accumulation of p21WAF1(Cip1 in human immature leukemic cells. Eur J Haematol 65(4):221–236

    Article  PubMed  CAS  Google Scholar 

  7. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ (2003) Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 171(1):88–95

    PubMed  CAS  Google Scholar 

  8. Wagenknecht B, Hermisson M, Eitel K, Weller M (1999) Proteasome inhibitors induce p53/p21-independent apoptosis in human glioma cells. Cell Physiol Biochem 9(3):117–125

    Article  PubMed  CAS  Google Scholar 

  9. Williams SA, McConkey DJ (2003) The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells. Cancer Res 63(21):7338–7344

    PubMed  CAS  Google Scholar 

  10. Yu C, Rahmani M, Dent P, Grant S (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295(2):555–566

    Article  PubMed  CAS  Google Scholar 

  11. Dewson G, Snowden RT, Almond JB, Dyer MJ, Cohen GM (2003) Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells. Oncogene 22(17):2643–2654

    Article  PubMed  CAS  Google Scholar 

  12. Drexler HC (1998) Programmed cell death and the proteasome. Apoptosis 3(1):1–7

    Article  PubMed  CAS  Google Scholar 

  13. Ling YH, Liebes L, Zou Y, Perez-Soler R (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278(36):33714–33723. Epub 2003 Jun 23

    Article  PubMed  CAS  Google Scholar 

  14. MacFarlane M, Merrison W, Bratton SB, Cohen GM (2002) Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J Biol Chem 277(39):36611–36616

    Article  PubMed  CAS  Google Scholar 

  15. Qiu JH, Asai A, Chi S, Saito N, Hamada H, Kirino T (2000) Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J Neurosci 20(1):259–265

    PubMed  CAS  Google Scholar 

  16. Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM (2004) Caspase activation inhibits proteasome function during apoptosis. Mol Cell 14(1):81–93

    Article  PubMed  CAS  Google Scholar 

  17. Yagita H, Takeda K, Hayakawa Y, Smyth MJ, Okumura K (2004) TRAIL and its receptors as targets for cancer therapy. Cancer Sci 95(10):777–783

    Article  PubMed  CAS  Google Scholar 

  18. Kelley SK, Ashkenazi A (2004) Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 4(4):333–339

    Article  PubMed  CAS  Google Scholar 

  19. Liabakk NB, Espevik T (2004) Monoclonal antibodies against TRAIL. Vitam Horm 67:65–79

    PubMed  Google Scholar 

  20. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S (1999) Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 59(3):734–741

    PubMed  CAS  Google Scholar 

  21. Ohtsuka T, Buchsbaum D, Oliver P, Makhija S, Kimberly R, Zhou T (2003) Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway. Oncogene 22(13):2034–2044

    Article  PubMed  CAS  Google Scholar 

  22. An J, Sun YP, Adams J, Fisher M, Belldegrun A, Rettig MB (2003) Drug interactions between the proteasome inhibitor bortezomib and cytotoxic chemotherapy, tumor necrosis factor (TNF) alpha, and TNF-related apoptosis-inducing ligand in prostate cancer. Clin Cancer Res 9(12):4537–4545

    PubMed  CAS  Google Scholar 

  23. 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(14):2554–2558

    Article  PubMed  CAS  Google Scholar 

  24. Johnson TR, Stone K, Nikrad M, Yeh T, Zong WX, Thompson CB, et al (2003) The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 22(32):4953–4963

    Article  PubMed  CAS  Google Scholar 

  25. Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, et al (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102(1):303–310

    Article  PubMed  CAS  Google Scholar 

  26. Gibson SB, Oyer R, Spalding AC, Anderson SM, Johnson GL (2000) Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol Cell Biol 20(1):205–212

    Article  PubMed  CAS  Google Scholar 

  27. Johnston JB, Kabore AF, Strutinsky J, Hu X, Paul JT, Kropp DM, et al (2003) Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene 22(51):8356–8369

    Article  PubMed  CAS  Google Scholar 

  28. Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ (2000) Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 60(4):847–853

    PubMed  CAS  Google Scholar 

  29. Sheikh MS, Burns TF, Huang Y, Wu GS, Amundson S, Brooks KS, et al (1998) p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Res 58(8):1593–1598

    PubMed  CAS  Google Scholar 

  30. Wu GS, Burns TF, McDonald ER 3rd, Meng RD, Kao G, Muschel R, et al (1999) Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 18(47):6411–6418

    Article  PubMed  CAS  Google Scholar 

  31. Wang S, El-Deiry WS (2003) TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22(53):8628–8633

    Article  PubMed  CAS  Google Scholar 

  32. Roth W, Reed JC (2004) FLIP protein and TRAIL-induced apoptosis. Vitam Horm 67:189–206.

    Article  PubMed  CAS  Google Scholar 

  33. Kay NE, Hamblin TJ, Jelinek DF, Dewald GW, Byrd JC, Farag S, et al (2002) Chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 193–213

  34. Almond JB, Snowden RT, Hunter A, Dinsdale D, Cain K, Cohen GM (2001) Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. Leukemia 15(9):1388–1397

    Article  PubMed  CAS  Google Scholar 

  35. Chandra J, Niemer I, Gilbreath J, Kliche KO, Andreeff M, Freireich EJ, et al (1998) Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood 92(11):4220–4229

    PubMed  CAS  Google Scholar 

  36. Kelley TW, Alkan S, Srkalovic G, Hsi ED (2004) Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis. Leuk Res 28(8):845–850

    Article  PubMed  CAS  Google Scholar 

  37. Pahler JC, Ruiz S, Niemer I, Calvert LR, Andreeff M, Keating M, et al (2003) Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. Clin Cancer Res 9(12):4570–4577

    PubMed  CAS  Google Scholar 

  38. Begleiter A, Verburg L, Ashique A, Lee K, Israels LG, Mowat MR, et al (1995) Comparison of antitumor activities of 2-chlorodeoxyadenosine and 9-beta-arabinosyl-2-fluoroadenine in chronic lymphocytic leukemia and marrow cells in vitro. Leukemia 9(11):1875–1881

    PubMed  CAS  Google Scholar 

  39. Begleiter A, Wang H, Verburg L, Lee K, Israels LG, Mowat MR, et al (1996) In vitro cytotoxicity of 2-chlorodeoxyadenosine and chlorambucil in chronic lymphocytic leukemia. Leukemia 10(12):1959–1965

    PubMed  CAS  Google Scholar 

  40. Wang S, El-Deiry WS (2004) Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res 64(18):6666–6672

    Article  PubMed  CAS  Google Scholar 

  41. Bogner C, Schneller F, Hipp S, Ringshausen I, Peschel C, Decker T (2003) Cycling B-CLL cells are highly susceptible to inhibition of the proteasome: Involvement of p27, early D-type cyclins, Bax, and caspase-dependent and -independent pathways. Exp Hematol 31(3):218–225

    Article  PubMed  CAS  Google Scholar 

  42. Jonsson G, Paulie S, Grandien A (2003) High level of cFLIP correlates with resistance to death receptor-induced apoptosis in bladder carcinoma cells. Anticancer Res 23(2B):1213–1218

    PubMed  Google Scholar 

  43. Yamada H, Tada-Oikawa S, Uchida A, Kawanishi S (1999) TRAIL causes cleavage of bid by caspase-8 and loss of mitochondrial membrane potential resulting in apoptosis in BJAB cells. Biochem Biophys Res Commun 265(1):130–133

    Article  PubMed  CAS  Google Scholar 

  44. Ehrhardt H, Fulda S, Schmid I, Hiscott J, Debatin KM, Jeremias I (2003) TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene 22(25):3842–3852

    Article  PubMed  CAS  Google Scholar 

  45. MacLaren AP, Chapman RS, Wyllie AH, Watson CJ (2001) p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells. Cell Death Differ 8(3):210–218

    Article  PubMed  CAS  Google Scholar 

  46. Nakaso K, Yoshimoto Y, Yano H, Takeshima T, Nakashima K (2004) p53-mediated mitochondrial dysfunction by proteasome inhibition in dopaminergic SH-SY5Y cells. Neurosci Lett 354(3):213–216

    Article  PubMed  CAS  Google Scholar 

  47. Dai Y, Rahmani M, Grant S (2003) Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 22(46):7108–7122

    Article  PubMed  CAS  Google Scholar 

  48. Delic J, Masdehors P, Omura S, Cosset JM, Dumont J, Binet JL, et al (1998) The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer 77(7):1103–1107

    PubMed  CAS  Google Scholar 

  49. Masdehors P, Omura S, Merle-Beral H, Mentz F, Cosset JM, Dumont J, et al (1999) Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br J Haematol 105(3):752–757

    Article  PubMed  CAS  Google Scholar 

  50. Shetty S, Gladden JB, Henson ES, Hu X, Villanueva J, Haney N, et al (2002) Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkappaB activation in epithelial derived cell lines. Apoptosis 7(5):413–420

    Article  PubMed  CAS  Google Scholar 

  51. Kreuz S, Siegmund D, Scheurich P, Wajant H (2001) NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol 21(12):3964–3973

    Article  PubMed  CAS  Google Scholar 

  52. Olsson A, Diaz T, Aguilar-Santelises M, Osterborg A, Celsing F, Jondal M, et al (2001) Sensitization to TRAIL-induced apoptosis and modulation of FLICE-inhibitory protein in B chronic lymphocytic leukemia by actinomycin D. Leukemia 15(12):1868–1877

    PubMed  CAS  Google Scholar 

  53. Luo H, Wu Y, Qi S, Wan X, Chen H, Wu J (2001) A proteasome inhibitor effectively prevents mouse heart allograft rejection. Transplantation 72(2):196–202

    Article  PubMed  CAS  Google Scholar 

  54. Sun K, Welniak LA, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Liu H, Barao I, et al (2004) Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA 101(21):8120–8125

    Article  PubMed  CAS  Google Scholar 

  55. MacFarlane M, Harper N, Snowden RT, Dyer MJ, Barnett GA, Pringle JH, et al (2002) Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene 21(44):6809–6818

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Manitoba Institute of Cell Biology, Cancer Care Manitoba, University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9

    Albert F. Kabore, Jinmie Sun, Xiaojie Hu, Kristin McCrea, James B. Johnston & Spencer B. Gibson

  2. Department of Internal Medicine, University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9

    James B. Johnston

  3. Department of Biochemistry and Medical Genetics, University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9

    Spencer B. Gibson

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  1. Albert F. Kabore
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  2. Jinmie Sun
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  3. Xiaojie Hu
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  4. Kristin McCrea
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  5. James B. Johnston
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  6. Spencer B. Gibson
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Correspondence to Spencer B. Gibson.

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Kabore, A.F., Sun, J., Hu, X. et al. The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis 11, 1175–1193 (2006). https://doi.org/10.1007/s10495-006-8048-9

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