Oncotarget

Priority Research Papers:

Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

Anusha Sriraman, Marija Radovanovic, Magdalena Wienken, Zeynab Najafova, Yizhu Li and Matthias Dobbelstein _

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Oncotarget. 2016; 7:31623-31638. https://doi.org/10.18632/oncotarget.9302

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Abstract

Anusha Sriraman1, Marija Radovanovic1, Magdalena Wienken1, Zeynab Najafova2, Yizhu Li1 and Matthias Dobbelstein1

1 Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany

2 Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany

Correspondence to:

Yizhu Li, email:

Matthias Dobbelstein, email:

Keywords: Mdm2, Wip1/PPM1D, p53, kinase, phosphatase

Received: February 13, 2016 Accepted: April 26, 2016 Published: May 11, 2016

Abstract

Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.


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