Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
| Autor: | Mark S. Cragg, Gordon K. Smyth, Marco J Herold, Andreas Strasser, Clare L. Scott, Lina Happo, Cassandra J. Vandenberg, Elisa S. Jansen, Jon M. Haga, Grant Dewson, Belinda Phipson, Suzanne Cory, Ewa M. Michalak |
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| Rok vydání: | 2010 |
| Předmět: |
Lymphoma
B-Cell Tumor suppressor gene DNA damage Immunology Apoptosis Biochemistry Cell therapy Mice Proto-Oncogene Proteins hemic and lymphatic diseases Puma medicine Animals Neoplasm Cyclophosphamide B cell Etoposide Mice Knockout Gene knockdown Lymphoid Neoplasia Bcl-2-Like Protein 11 biology Tumor Suppressor Proteins Membrane Proteins Cell Biology Hematology medicine.disease biology.organism_classification Lymphoma medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm Cancer research biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins DNA Damage |
| Zdroj: | Blood. 116:5256-5267 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic. |
| Databáze: | OpenAIRE |
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