Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells
Nutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716300377 |
| _version_ | 1818082814139039744 |
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| author | Liz J. Valente Brandon J. Aubrey Marco J. Herold Gemma L. Kelly Lina Happo Clare L. Scott Andrea Newbold Ricky W. Johnstone David C.S. Huang Lyubomir T. Vassilev Andreas Strasser |
| author_facet | Liz J. Valente Brandon J. Aubrey Marco J. Herold Gemma L. Kelly Lina Happo Clare L. Scott Andrea Newbold Ricky W. Johnstone David C.S. Huang Lyubomir T. Vassilev Andreas Strasser |
| author_sort | Liz J. Valente |
| collection | DOAJ |
| description | Nutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted mouse models lacking the critical p53 target genes, p21, Puma, and Noxa, we found that only loss of PUMA conferred profound protection against Nutlin3a-induced killing in both non-transformed lymphoid cells and Eμ-Myc lymphomas in vitro and in vivo. CRISPR/Cas9-mediated targeting of the PUMA gene rendered human hematopoietic cancer cell lines markedly resistant to Nutlin3a-induced cell death. These results demonstrate that PUMA-mediated apoptosis, but not p21-mediated cell-cycle arrest or senescence, is a critical determinant of the therapeutic response to non-genotoxic p53 activation by Nutlin3a. Importantly, in human cancer, PUMA expression may predict patient responses to treatment with MDM2 antagonists. |
| first_indexed | 2024-12-10T19:28:04Z |
| format | Article |
| id | doaj.art-52a55445e4b54bfcb568bd86fe2147c2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T19:28:04Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-52a55445e4b54bfcb568bd86fe2147c22022-12-22T01:36:20ZengElsevierCell Reports2211-12472016-03-011481858186610.1016/j.celrep.2016.01.059Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma CellsLiz J. Valente0Brandon J. Aubrey1Marco J. Herold2Gemma L. Kelly3Lina Happo4Clare L. Scott5Andrea Newbold6Ricky W. Johnstone7David C.S. Huang8Lyubomir T. Vassilev9Andreas Strasser10The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaCancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, AustraliaCancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaDiscovery Oncology, Hoffmann-La Roche Inc., Nutley, NJ 07110, USAThe Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, AustraliaNutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted mouse models lacking the critical p53 target genes, p21, Puma, and Noxa, we found that only loss of PUMA conferred profound protection against Nutlin3a-induced killing in both non-transformed lymphoid cells and Eμ-Myc lymphomas in vitro and in vivo. CRISPR/Cas9-mediated targeting of the PUMA gene rendered human hematopoietic cancer cell lines markedly resistant to Nutlin3a-induced cell death. These results demonstrate that PUMA-mediated apoptosis, but not p21-mediated cell-cycle arrest or senescence, is a critical determinant of the therapeutic response to non-genotoxic p53 activation by Nutlin3a. Importantly, in human cancer, PUMA expression may predict patient responses to treatment with MDM2 antagonists.http://www.sciencedirect.com/science/article/pii/S2211124716300377 |
| spellingShingle | Liz J. Valente Brandon J. Aubrey Marco J. Herold Gemma L. Kelly Lina Happo Clare L. Scott Andrea Newbold Ricky W. Johnstone David C.S. Huang Lyubomir T. Vassilev Andreas Strasser Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells Cell Reports |
| title | Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells |
| title_full | Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells |
| title_fullStr | Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells |
| title_full_unstemmed | Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells |
| title_short | Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells |
| title_sort | therapeutic response to non genotoxic activation of p53 by nutlin3a is driven by puma mediated apoptosis in lymphoma cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716300377 |
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