| Noxa mediates bortezomib induced apoptosis in both sensitive and intrinsically resistant mantle cell lymphoma cells and this effect is independent of constitutive activity of the AKT and NF-kappaB pathways. | |
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MedLine Citation:
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PMID: 18398749 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Bortezomib is more active against mantle cell lymphoma (MCL) than against most other lymphoma subtypes. Nevertheless, up to half of patients with MCL have bortezomib resistant disease. Factors contributing to intrinsic resistance to bortezomib have not been determined. Here we used a panel of eight bortezomib sensitive (median IC(50) 5.9 nM) and three relatively bortezomib resistant cell lines (median IC(50) 12.9 nM) to investigate differences in tumor biology that could determine sensitivity to bortezomib. Bortezomib effectively inhibited high baseline proteasome activity and induced a comparable degree of proteasome inhibition in both sensitive and resistant cells. At 10 nM, bortezomib induced the proapoptotic BH3-only protein Noxa in sensitive but not resistant cells. At higher concentrations of bortezomib, however, Noxa was also upregulated in resistant cells and this effect was sufficient to induce apoptosis. Silencing of Noxa with siRNA rescued these cells from apoptosis, arguing against a defect in Noxa regulation or function as the basis of bortezomib resistance. Bortezomib was equally effective against cells with high and low constitutive NF-kappaB signaling. Also, sensitive and resistant MCL cell lines showed comparable activation of the AKT pathway. We conclude that bortezomib can overcome classic mechanisms of resistance to apoptosis and that determinants of bortezomib sensitivity in MCL are due to differences in signaling or stress pathways upstream of Noxa. |
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Authors:
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Edgar Gil Rizzatti; Helena Mora-Jensen; Marc Andrée Weniger; Federica Gibellini; Elinor Lee; Masanori Daibata; Raymond Lai; Adrian Wiestner |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural |
Journal Detail:
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Title: Leukemia & lymphoma Volume: 49 ISSN: 1029-2403 ISO Abbreviation: Leuk. Lymphoma Publication Date: 2008 Apr |
Date Detail:
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Created Date: 2008-04-09 Completed Date: 2008-08-04 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9007422 Medline TA: Leuk Lymphoma Country: England |
Other Details:
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Languages: eng Pagination: 798-808 Citation Subset: IM |
Affiliation:
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Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Boronic Acids / pharmacology* Cell Line, Tumor Dose-Response Relationship, Drug Humans Lymphoma, Mantle-Cell / drug therapy, pathology* NF-kappa B / metabolism* Proto-Oncogene Proteins c-akt / metabolism* Proto-Oncogene Proteins c-bcl-2 / genetics, physiology* Pyrazines / pharmacology* Signal Transduction Up-Regulation |
| Chemical | |
Reg. No./Substance:
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0/Boronic Acids; 0/NF-kappa B; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazines; 0/bortezomib; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
| Comments/Corrections | |
Comment In:
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Leuk Lymphoma. 2008 Apr;49(4):657-8
[PMID:
18398731
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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