MDM2-Dependent Downregulation of p21 and hnRNP K Provides a Switch between Apoptosis and Growth Arrest Induced by Pharmacologically Activated p53

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Cancer cell (Impact Factor: 23.52). 04/2009; 15(3):171-83. DOI: 10.1016/j.ccr.2009.01.019
Source: PubMed

ABSTRACT We have previously identified the p53-reactivating compound RITA in a cell-based screen. Here, using microarray analysis, we show that the global transcriptional response of tumor cells to RITA is p53 dependent. Pathway analysis revealed induction of the p53 apoptosis pathway, consistent with apoptosis being the major response to RITA in cancer cells. We uncovered that MDM2 released from p53 by RITA promotes degradation of p21 and the p53 cofactor hnRNP K, required for p21 transcription. Functional studies revealed MDM2-dependent inhibition of p21 as a key switch regulating cell fate decisions upon p53 reactivation. Our results emphasize the utility of targeting wild-type p53 protein itself as a promising approach for anticancer therapy.

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Available from: Galina Selivanova, Sep 25, 2015
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    • "One compound of interest, RITA (reactivation of p53 and induction of tumor cell apoptosis), is a small molecule that binds to the N-terminus of the p53 protein and induces a conformational change that can lead to restoration of normal p53 function [11], [12]. RITA can activate p53 downstream targets in both p53 wt [13], [14] and p53 mutant (mt) cells [15] in a variety of models. "
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    ABSTRACT: TP53 is the most commonly mutated gene in head and neck cancer (HNSCC), with mutations being associated with resistance to conventional therapy. Restoring normal p53 function has previously been investigated via the use of RITA (reactivation of p53 and induction of tumor cell apoptosis), a small molecule that induces a conformational change in p53, leading to activation of its downstream targets. In the current study we found that RITA indeed exerts significant effects in HNSCC cells. However, in this model, we found that a significant outcome of RITA treatment was accelerated senescence. RITA-induced senescence in a variety of p53 backgrounds, including p53 null cells. Also, inhibition of p53 expression did not appear to significantly inhibit RITA-induced senescence. Thus, this phenomenon appears to be partially p53-independent. Additionally, RITA-induced senescence appears to be partially mediated by activation of the DNA damage response and SIRT1 (Silent information regulator T1) inhibition, with a synergistic effect seen by combining either ionizing radiation or SIRT1 inhibition with RITA treatment. These data point toward a novel mechanism of RITA function as well as hint to its possible therapeutic benefit in HNSCC.
    PLoS ONE 08/2014; 9(8):e104821. DOI:10.1371/journal.pone.0104821 · 3.23 Impact Factor
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    • "Upon binding to p53, RITA reactivates it and induces apoptosis by disrupting the interaction with MDM2 [25,30]. Although the IC50 values for RITA vary depending on tumor cell type, growth inhibition is clearly more effective in wild type p53-expressing cells [25,30,80-87]. "
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    ABSTRACT: p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative effects of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor activities in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.
    Journal of Hematology & Oncology 03/2013; 6(1):23. DOI:10.1186/1756-8722-6-23 · 4.81 Impact Factor
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    • "Interestingly, p53 induction by nutlin-3 resulted in a consistent antiproliferative effect in p53 wild-type GIST but not in a strong induction of apoptosis. As hypothesized by Enge et al, this may be due to the induction of the anti-apoptotic protein p21, which was seen after nutlin-3 but not after RITA treatment (Fig. 3) [19]. Our findings suggest that in the GIST context, when given alone, nutlin-3 induces cell cycle arrest rather than apoptosis (FigS2). "
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    ABSTRACT: The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response.
    PLoS ONE 05/2012; 7(5):e37776. DOI:10.1371/journal.pone.0037776 · 3.23 Impact Factor
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