Therapeutic response to non-genotoxic activation of p53 by nutlin3a is driven by puma-mediated apoptosis in lymphoma cells
- Author(s)
- Valente, LJ; Aubrey, BJ; Herold, MJ; Kelly, GL; Happo, L; Scott, CL; Newbold, A; Johnstone, RW; Huang, DC; Vassilev, LT; Strasser, A;
- Details
- Publication Year 2016-03-01,Volume 14,Issue #8,Page 1858-66
- Journal Title
- Cell Rep
- Publication Type
- Journal Article
- Abstract
- 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 Emu-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.
- Publisher
- Cell Press
- Research Division(s)
- Molecular Genetics Of Cancer; Stem Cells And Cancer; Cancer And Haematology
- PubMed ID
- 26904937
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2016.01.059
- Open Access at Publisher's Site
http://www.sciencedirect.com/science/article/pii/S2211124716300377- NHMRC Grants
- NHMRC/1016701, NHMRC/1046010, NHMRC/637326, NHMRC/1020363,
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- Refer to copyright notice on published article.
Creation Date: 2016-03-15 03:47:47
Last Modified: 2016-03-16 09:53:49