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Blood, 1 January 2006, Vol. 107, No. 1, pp. 257-264.
Prepublished online as a Blood First Edition Paper on September 15, 2005; DOI 10.1182/blood-2005-05-2091.
Previous Article | Table of Contents | Next Article 
NEOPLASIA
The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status
Patricia Pérez-Galán,
Gaël Roué,
Neus Villamor,
Emili Montserrat,
Elias Campo, and
Dolors Colomer
From the Hematopathology Unit, Departments of Pathology and Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Mantle-cell lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib is a novel, reversible, and highly specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in 4 MCL cell lines and in primary tumor cells from 10 MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes, and caspase activation. In addition, ROS scavengers, but not pancaspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA-expression analysis, revealed marked up-regulation of the BH3-only protein Noxa, between 4 to 6 hours after bortezomib addition, independent of p53 status. However, this up-regulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the antiapoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that up-regulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.

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|
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|
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|
 |
|

|
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|
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|

|
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|
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|
 |
|

|
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|
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111(3):
1617 - 1624.
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[Full Text]
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|
 |
|

|
 |

|
 |
 
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Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis
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December 4, 2007;
104(49):
19512 - 19517.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. A. Nikiforov, M. Riblett, W.-H. Tang, V. Gratchouck, D. Zhuang, Y. Fernandez, M. Verhaegen, S. Varambally, A. M. Chinnaiyan, A. J. Jakubowiak, et al.
Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition
PNAS,
December 4, 2007;
104(49):
19488 - 19493.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. P. Miller, K. Ban, M. E. Dujka, D. J. McConkey, M. Munsell, M. Palladino, and J. Chandra
NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells
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July 1, 2007;
110(1):
267 - 277.
[Abstract]
[Full Text]
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|
 |
|

|
 |

|
 |
 
J. Voortman, E. F. Smit, R. Honeywell, B. C. Kuenen, G. J. Peters, H. van de Velde, and G. Giaccone
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June 15, 2007;
13(12):
3642 - 3651.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Gomez-Bougie, S. Wuilleme-Toumi, E. Menoret, V. Trichet, N. Robillard, M. Philippe, R. Bataille, and M. Amiot
Noxa Up-regulation and Mcl-1 Cleavage Are Associated to Apoptosis Induction by Bortezomib in Multiple Myeloma
Cancer Res.,
June 1, 2007;
67(11):
5418 - 5424.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Koschny, H. Holland, J. Sykora, T. L. Haas, M. R. Sprick, T. M. Ganten, W. Krupp, M. Bauer, P. Ahnert, J. Meixensberger, et al.
Bortezomib Sensitizes Primary Human Astrocytoma Cells of WHO Grades I to IV for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis
Clin. Cancer Res.,
June 1, 2007;
13(11):
3403 - 3412.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Perez-Galan, G. Roue, N. Villamor, E. Campo, and D. Colomer
The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak
Blood,
May 15, 2007;
109(10):
4441 - 4449.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Voortman, A. Checinska, G. Giaccone, J. A. Rodriguez, and F. A.E. Kruyt
Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non-small cell lung cancer cell line NCI-H460
Mol. Cancer Ther.,
March 1, 2007;
6(3):
1046 - 1053.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
W.-X. Ding, H.-M. Ni, X. Chen, J. Yu, L. Zhang, and X.-M. Yin
A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells
Mol. Cancer Ther.,
March 1, 2007;
6(3):
1062 - 1069.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. A. Smit, D. Y.H. Hallaert, R. Spijker, B. de Goeij, A. Jaspers, A. P. Kater, M. H.J. van Oers, C. J.M. van Noesel, and E. Eldering
Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity
Blood,
February 15, 2007;
109(4):
1660 - 1668.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Roue, P. Perez-Galan, M. Lopez-Guerra, N. Villamor, E. Campo, and D. Colomer
Selective Inhibition of I{kappa}B Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level
J. Immunol.,
February 1, 2007;
178(3):
1923 - 1930.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Mestre-Escorihuela, F. Rubio-Moscardo, J. A. Richter, R. Siebert, J. Climent, V. Fresquet, E. Beltran, X. Agirre, I. Marugan, M. Marin, et al.
Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas
Blood,
January 1, 2007;
109(1):
271 - 280.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. I. Fisher, S. H. Bernstein, B. S. Kahl, B. Djulbegovic, M. J. Robertson, S. de Vos, E. Epner, A. Krishnan, J. P. Leonard, S. Lonial, et al.
Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma
J. Clin. Oncol.,
October 20, 2006;
24(30):
4867 - 4874.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. M. Fribley, B. Evenchik, Q. Zeng, B. K. Park, J. Y. Guan, H. Zhang, T. J. Hale, M. S. Soengas, R. J. Kaufman, and C.-Y. Wang
Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa
J. Biol. Chem.,
October 20, 2006;
281(42):
31440 - 31447.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. Aleo, C. J. Henderson, A. Fontanini, B. Solazzo, and C. Brancolini
Identification of new compounds that trigger apoptosome-independent caspase activation and apoptosis.
Cancer Res.,
September 15, 2006;
66(18):
9235 - 9244.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Yu, B. B. Friday, J.-P. Lai, L. Yang, J. Sarkaria, N. E. Kay, C. A. Carter, L. R. Roberts, S. H. Kaufmann, and A. A. Adjei
Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways.
Mol. Cancer Ther.,
September 1, 2006;
5(9):
2378 - 2387.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Rudelius, S. Pittaluga, S. Nishizuka, T. H.-T. Pham, F. Fend, E. S. Jaffe, L. Quintanilla-Martinez, and M. Raffeld
Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma
Blood,
September 1, 2006;
108(5):
1668 - 1676.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
X. Dolcet, D. Llobet, M. Encinas, J. Pallares, A. Cabero, J. A. Schoenenberger, J. X. Comella, and X. Matias-Guiu
Proteasome Inhibitors Induce Death but Activate NF-{kappa}B on Endometrial Carcinoma Cell Lines and Primary Culture Explants
J. Biol. Chem.,
August 4, 2006;
281(31):
22118 - 22130.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Marce, O. Balague, L. Colomo, A. Martinez, S. Holler, N. Villamor, F. Bosch, G. Ott, A. Rosenwald, L. Leoni, et al.
Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy.
Clin. Cancer Res.,
June 15, 2006;
12(12):
3754 - 3761.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|
|