IGF-1R/MDM2 Relationship Confers Enhanced Sensitivity to RITA in Ewing Sarcoma Cells

Conza, Giusy Di; Buttarelli, Marianna; Monti, Olimpia; Pellegrino, Marsha; Mancini, Francesca; Pontecorvi, Alfredo; Scotlandi, Katia; Moretti, Fabiola

doi:10.1158/1535-7163.mct-11-0913

Cited by 18 publications

(19 citation statements)

References 47 publications

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“…Of note, nutlin3a does not kill HCT116 cells but induces cell-cycle arrest, in contrast to RITA, which kills the cells. A recent publication demonstrated that RITA killed Ewing sarcoma cells independently of p53 through the degradation of IGF1R [34]. This mechanism is unlikely to occur in myeloma cells because we did not observe any modulation of IGF1R expression (data not shown) and we previously showed that blocking IGF1R signaling induced cell growth arrest but not cell death [35].…”

Section: Discussionmentioning

confidence: 49%

RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53 abnormal myeloma cells independently of the p53 pathway

et al. 2014

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BackgroundThe aim of this study was to evaluate the efficacy of the p53-reactivating drugs RITA and nutlin3a in killing myeloma cells.MethodsA large cohort of myeloma cell lines (n = 32) and primary cells (n = 21) was used for this study. This cohort contained cell lines with various TP53 statuses and primary cells with various incidences of deletion of chromosome 17. Apoptosis was evaluated using flow cytometry with Apo2.7 staining of the cell lines or via the loss of the myeloma-specific marker CD138 in primary cells. Apoptosis was further confirmed by the appearance of a subG1 peak and the activation of caspases 3 and 9. Activation of the p53 pathway was monitored using immunoblotting via the expression of the p53 target genes p21, Noxa, Bax and DR5. The involvement of p53 was further studied in 4 different p53-silenced cell lines.ResultsBoth drugs induced the apoptosis of myeloma cells. The apoptosis that was induced by RITA was not related to the TP53 status of the cell lines or the del17p status of the primary samples (p = 0.52 and p = 0.80, respectively), and RITA did not commonly increase the expression level of p53 or p53 targets (Noxa, p21, Bax or DR5) in sensitive cells. Moreover, silencing of p53 in two TP53mutated cell lines failed to inhibit apoptosis that was induced by RITA, which confirmed that RITA-induced apoptosis in myeloma cells was p53 independent. In contrast, apoptosis induced by nutlin3a was directly linked to the TP53 status of the cell lines and primary samples (p < 0.001 and p = 0.034, respectively) and nutlin3a increased the level of p53 and p53 targets in a p53-dependent manner. Finally, we showed that a nutlin3a-induced DR5 increase (≥1.2-fold increase) was a specific and sensitive marker (p < 0.001) for a weak incidence of 17p deletion within the samples (≤19%).ConclusionThese data show that RITA, in contrast to nutlin3a, effectively induced apoptosis in a subset of MM cells independently of p53. The findings and could be of interest for patients with a 17p deletion, who are resistant to current therapies.

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Section: Discussionmentioning

confidence: 49%

RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53 abnormal myeloma cells independently of the p53 pathway

et al. 2014

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“…Moreover, RITA might even have p53-independent effects. 34 Noteworthy, RITA was proved to inhibit several oncogenes and survival genes, including MYC and AKT, specifically in cancer cells, 53 which is tantalizing considering the heterogeneity of genetic alterations in tumors. More recently, RITA was shown to sensitize tumor cells to agents that induce oxidative stress through a p53-dependent inhibition of thioredoxin reductase 1 (TrxR1), a key enzyme of the thioredoxin system, which protects cells from oxidative damage.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, these findings suggest that p53 is capable, at least in part, of mediating RITA cytotoxic effect on mesothelioma cell lines also when its activity is partially impaired by mutation (in IST-MES 2 and NCI-H2452). This seems to indicate that, although RITA probably acts through different mechanisms, 34 RITA-mediated p53 reactivation is indeed crucial for the induction of apoptosis in sensitive mesothelioma cell lines.…”

Section: Rita Induces Apoptosis In Epithelioid and Biphasic Mesothelimentioning

confidence: 95%

Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

et al. 2013

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“…RITA binding is proposed to induce a conformational change in p53, resulting in its dissociation from Mdm2 (243). However, it has also been shown that RITA causes DNA-protein crosslinks and is metabolized to a reactive species, leading to p53-independent toxicity (244–246). …”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

Carr¹,

Jones²

2016

Transl. Cancer Res.

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The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function. Although regulation of p53 levels and function is coordinated by many proteins, it is now widely accepted that the master regulator of p53 is Mdm2. In this review, we discuss the role(s) of p53 in the DNA damage response and in tumor suppression, and how post-translational modification of Mdm2 regulates the Mdm2-p53 signaling axis to govern p53 activities in the cell.

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IGF-1R/MDM2 Relationship Confers Enhanced Sensitivity to RITA in Ewing Sarcoma Cells

Cited by 18 publications

References 47 publications

RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53 abnormal myeloma cells independently of the p53 pathway

RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53 abnormal myeloma cells independently of the p53 pathway

Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

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