Home LiteratureArticle Details
PMID: 18489772 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma.

Molecular cancer ·Vol. 7 ·2008-05-19 ·Pages 40

Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S

Abstract

The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-kappaB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). However, NF-kappaB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-kappaB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-kappaB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-kappaB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-kappaB activity. Our findings show that bortezomib-resistant NF-kappaB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.

MeSH Terms
Aged Aged, 80 and over Animals Antineoplastic Agents/pharmacology Boronic Acids/pharmacology Bortezomib Cell Line, Tumor Drug Resistance, Neoplasm Electrophoretic Mobility Shift Assay Female Humans Lymphoma, Mantle-Cell/metabolism,pathology Male Middle Aged NF-kappa B/metabolism Proteasome Endopeptidase Complex/metabolism Proteasome Inhibitors Pyrazines/pharmacology
Chemicals
Antineoplastic Agents Boronic Acids NF-kappa B Proteasome Inhibitors Pyrazines Bortezomib Proteasome Endopeptidase Complex
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yang David T
Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, USA. dtyang@wisc.edu
Young Ken H
Kahl Brad S
Markovina Stephanie
Miyamoto Shigeki
References (80)
80 references, click to expand
  1. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis.
    J Immunol. 2003 Jul 1;171(1):88-95 PMID: 12816986
  2. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG).
    Blood. 2006 Dec 15;108(13):4003-8 PMID: 16946304
  3. Molecular sequelae of proteasome inhibition in human multiple myeloma cells.
    Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14374-9 PMID: 12391322
  4. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100.
    Mol Cell. 2001 Feb;7(2):401-9 PMID: 11239468
  5. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.
    J Clin Oncol. 2005 Feb 1;23(4):667-75 PMID: 15613697
  6. Mantle cell lymphoma: a clinicopathologic study of 80 cases.
    Blood. 1997 Mar 15;89(6):2067-78 PMID: 9058729
  7. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.
    Cancer Cell. 2007 Aug;12(2):115-30 PMID: 17692804
  8. Regulation of constitutive p50/c-Rel activity via proteasome inhibitor-resistant IkappaBalpha degradation in B cells.
    Mol Cell Biol. 2004 Jun;24(11):4895-908 PMID: 15143182
  9. Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IkappaB alpha/NF-kappaB pathway in limb-girdle muscular dystrophy type 2A.
    Nat Med. 1999 May;5(5):503-11 PMID: 10229226
  10. Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa.
    J Biol Chem. 2006 Oct 20;281(42):31440-7 PMID: 16928686
  11. Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines.
    Clin Cancer Res. 2003 Mar;9(3):1145-54 PMID: 12631620
  12. NF-kappaB1 can inhibit v-Abl-induced lymphoid transformation by functioning as a negative regulator of cyclin D1 expression.
    Mol Cell Biol. 2002 Aug;22(15):5563-74 PMID: 12101248
  13. Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites.
    J Biol Chem. 1991 Sep 15;266(26):17679-85 PMID: 1894647
  14. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.
    Cancer Cell. 2007 Aug;12(2):131-44 PMID: 17692805
  15. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine.
    J Clin Oncol. 2005 Oct 1;23(28):7013-23 PMID: 16145068
  16. Biology and therapy of mantle cell lymphoma.
    Curr Opin Oncol. 2005 Sep;17(5):425-31 PMID: 16093790
  17. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy.
    Oncologist. 2003;8(6):508-13 PMID: 14657528
  18. A phase 2 study of bortezomib in relapsed, refractory myeloma.
    N Engl J Med. 2003 Jun 26;348(26):2609-17 PMID: 12826635
  19. Approval summary for bortezomib for injection in the treatment of multiple myeloma.
    Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3954-64 PMID: 15217925
  20. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status.
    Blood. 2006 Jan 1;107(1):257-64 PMID: 16166592
  21. Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells.
    Mol Cell Biol. 2004 Nov;24(22):9695-704 PMID: 15509775
  22. Inhibitors of mammalian G1 cyclin-dependent kinases.
    Genes Dev. 1995 May 15;9(10):1149-63 PMID: 7758941
  23. Deregulated NF-kappaB activity in haematological malignancies.
    Biochem Pharmacol. 2006 Oct 30;72(9):1069-80 PMID: 16854381
  24. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival.
    J Clin Oncol. 2002 Mar 1;20(5):1288-94 PMID: 11870171
  25. Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells.
    Blood. 1999 Apr 1;93(7):2360-8 PMID: 10090947
  26. IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy.
    J Clin Invest. 2005 Oct;115(10):2625-32 PMID: 16200195
  27. Mantle cell lymphoma: from pathology and molecular pathogenesis to new therapeutic perspectives.
    Haematologica. 2006 Jan;91(1):11-6 PMID: 16434365
  28. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network.
    Ann Oncol. 2006 Sep;17(9):1418-23 PMID: 16766582
  29. Qualitative changes in the subunit composition of kappa B-binding complexes during murine B-cell differentiation.
    Proc Natl Acad Sci U S A. 1994 May 24;91(11):5056-60 PMID: 8197184
  30. Oxidative stress induces NF-kappaB nuclear translocation without degradation of IkappaBalpha.
    Circulation. 1999 Nov 9;100(19 Suppl):II361-4 PMID: 10567330
  31. Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors.
    Eur J Biochem. 1981 Mar 16;115(1):207-16 PMID: 7227366
  32. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells.
    J Exp Med. 2001 Dec 17;194(12):1861-74 PMID: 11748286
  33. Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo.
    Cancer Res. 1999 Jul 15;59(14):3468-74 PMID: 10416612
  34. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway.
    Science. 2001 Aug 24;293(5534):1495-9 PMID: 11520989
  35. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.
    Adv Enzyme Regul. 1984;22:27-55 PMID: 6382953
  36. Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors.
    Cancer. 2006 Nov 15;107(10):2482-9 PMID: 17036355
  37. NF-kappaB and IKK as therapeutic targets in cancer.
    Cell Death Differ. 2006 May;13(5):738-47 PMID: 16485028
  38. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma.
    J Clin Oncol. 2005 Feb 1;23(4):676-84 PMID: 15613699
  39. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.
    J Clin Oncol. 2002 Nov 15;20(22):4420-7 PMID: 12431963
  40. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.
    Blood. 1997 Jun 1;89(11):3909-18 PMID: 9166827
  41. Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol.
    Cancer Res. 1995 Mar 1;55(5):979-83 PMID: 7867007
  42. A switch in distinct I kappa B alpha degradation mechanisms mediates constitutive NF-kappa B activation in mature B cells.
    J Immunol. 2000 May 1;164(9):4762-7 PMID: 10779782
  43. Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation.
    J Biol Chem. 1999 Jan 8;274(2):787-94 PMID: 9873017
  44. A mechanistic insight into a proteasome-independent constitutive inhibitor kappaBalpha (IkappaBalpha) degradation and nuclear factor kappaB (NF-kappaB) activation pathway in WEHI-231 B-cells.
    Biochem J. 2004 May 15;380(Pt 1):173-80 PMID: 14763901
  45. Novel IkappaB alpha proteolytic pathway in WEHI231 immature B cells.
    Mol Cell Biol. 1998 Jan;18(1):19-29 PMID: 9418849
  46. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma.
    Biochem Pharmacol. 2005 Sep 1;70(5):700-13 PMID: 16023083
  47. Effects of the antitumor agent perillyl alcohol on H-Ras vs. K-Ras farnesylation and signal transduction in pancreatic cells.
    Anticancer Res. 1998 Mar-Apr;18(2A):823-8 PMID: 9615726
  48. Bortezomib: proteasome inhibition as an effective anticancer therapy.
    Annu Rev Med. 2006;57:33-47 PMID: 16409135
  49. Cancer chemoprevention and therapy by monoterpenes.
    Environ Health Perspect. 1997 Jun;105 Suppl 4:977-9 PMID: 9255590
  50. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer.
    J Clin Invest. 1997 Dec 15;100(12):2952-60 PMID: 9399940
  51. CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response.
    Mol Cell. 2003 Oct;12(4):829-39 PMID: 14580335
  52. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells.
    J Clin Invest. 1997 Dec 15;100(12):2961-9 PMID: 9399941
  53. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study.
    Blood. 1995 Feb 15;85(4):1075-82 PMID: 7849295
  54. Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha.
    EMBO J. 2001 Dec 3;20(23):6805-15 PMID: 11726516
  55. Missing pieces in the NF-kappaB puzzle.
    Cell. 2002 Apr;109 Suppl:S81-96 PMID: 11983155
  56. Signaling to NF-kappaB.
    Genes Dev. 2004 Sep 15;18(18):2195-224 PMID: 15371334
  57. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150.
    Ann Oncol. 2007 Jan;18(1):116-121 PMID: 16971665
  58. Supravital exposure to propidium iodide identifies apoptotic cells in the absence of nucleosomal DNA fragmentation.
    Cytometry. 1996 Apr 1;23(4):303-11 PMID: 8900473
  59. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells.
    Clin Cancer Res. 1999 Jan;5(1):119-27 PMID: 9918209
  60. Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors.
    Cancer. 1998 Feb 1;82(3):567-75 PMID: 9452276
  61. Transforming growth factor beta and cell cycle regulation.
    Cancer Res. 1995 Apr 1;55(7):1452-7 PMID: 7882352
  62. Nuclear factor-kappaB in cancer development and progression.
    Nature. 2006 May 25;441(7092):431-6 PMID: 16724054
  63. Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity.
    J Clin Oncol. 2006 May 1;24(13):2105-12 PMID: 16606971
  64. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network.
    Blood. 2005 Apr 1;105(7):2677-84 PMID: 15591112
  65. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma.
    Br J Haematol. 2004 Oct;127(2):165-72 PMID: 15461622
  66. Evidence for a phosphorylation-independent role for Ser 32 and 36 in proteasome inhibitor-resistant (PIR) IkappaBalpha degradation in B cells.
    Exp Cell Res. 2005 Jul 1;307(1):15-25 PMID: 15922723
  67. Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene.
    Cancer Chemother Pharmacol. 1994;34(6):477-83 PMID: 7923558
  68. Evidence for unique calmodulin-dependent nuclear factor-kappaB regulation in WEHI-231 B cells.
    Mol Pharmacol. 2002 Jan;61(1):177-85 PMID: 11752219
  69. Detection and localization of calpain 3-like protease in a neuronal cell line: possible regulation of apoptotic cell death through degradation of nuclear IkappaBalpha.
    Int J Biochem Cell Biol. 2006;38(12):2128-40 PMID: 16938483
  70. Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer.
    Cancer Res. 2003 May 1;63(9):2206-15 PMID: 12727841
  71. LMP-1 activates NF-kappa B by targeting the inhibitory molecule I kappa B alpha.
    J Virol. 1995 Apr;69(4):2168-74 PMID: 7884865
  72. Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol.
    Cancer Lett. 1995 Sep 4;96(1):15-21 PMID: 7553603
  73. Perillyl alcohol inhibits a calcium-dependent constitutive nuclear factor-kappaB pathway.
    Cancer Res. 2005 Sep 15;65(18):8558-66 PMID: 16166337
  74. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG).
    J Clin Oncol. 2005 Mar 20;23(9):1984-92 PMID: 15668467
  75. Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas.
    Blood. 2006 Jun 1;107(11):4540-8 PMID: 16497967
  76. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.
    J Clin Oncol. 2004 Jun 1;22(11):2108-21 PMID: 15169797
  77. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.
    Blood. 2003 Feb 15;101(4):1530-4 PMID: 12393500
  78. Cancer statistics, 2007.
    CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66 PMID: 17237035
  79. Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects.
    Toxicol Appl Pharmacol. 2004 Mar 1;195(2):232-46 PMID: 14998688
  80. Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group.
    Cancer. 2006 Sep 1;107(5):1014-22 PMID: 16878325
Article Info
Journal
Molecular cancer
Abbr.
Mol Cancer
ISSN
1476-4598
DOI
10.1186/1476-4598-7-40
Email
dtyang@wisc.edu
Published
2008-05-19
Epub
2008-00-19
Pages
40
Language
English
Region
England
NLM ID
101147698
PMCID
PMC2408930
Subset
IM
Grants
NCI NIH HHS · R01 CA077474 · United States
NCI NIH HHS · T32 CA009614 · United States
NIGMS NIH HHS · T32 GM008692 · United States
NCI NIH HHS · R01-CA08106 · United States
External Links
PubMed source DOI: 10.1186/1476-4598-7-40 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2