PRIMA-1 cytotoxicity correlates with nucleolar localization and degradation of mutant p53 in breast cancer cells

Russo, Debora; Ottaggio, Laura; Penna, Ilaria; Foggetti, Giorgia; Fronza, Gilberto; Inga, Alberto; Menichini, Paola

doi:10.1016/j.bbrc.2010.10.031

Cited by 20 publications

(19 citation statements)

References 27 publications

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“…3B). Additionally, although reported previously (34,35) with the time of treatment employed here (16 h), we did not observe a representative number of cells with p53 nucleolar staining upon PRIMA-1 treatment. MCF-7 cells present a markedly lower level of amyloid oligomer and p53 labeling, as reported previously (7) (Fig.…”

Section: Prima-1 Lowers Amyloid Oligomers Levels In Mutant P53 Cancercontrasting

confidence: 90%

p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells

Rangel

Ferretti

Costa

et al. 2019

Journal of Biological Chemistry

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Edited by Paul E. Fraser p53 mutants can form amyloid-like structures that accumulate in cells. p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) and its primary active metabolite, 2-methylene-3-quinuclidinone (MQ), can restore unfolded p53 mutants to a native conformation that induces apoptosis and activates several p53 target genes. However, whether PRIMA-1 can clear p53 aggregates is unclear. In this study, we investigated whether PRIMA-1 can restore aggregated mutant p53 to a native form. We observed that the p53 mutant protein is more sensitive to both PRIMA-1 and MQ aggregation inhibition than WT p53. The results of anti-amyloid oligomer antibody assays revealed that PRIMA-1 reverses mutant p53 aggregate accumulation in cancer cells. Size-exclusion chromatography of the lysates from mutant p53-containing breast cancer and ovarian cell lines confirmed that PRIMA-1 substantially decreases p53 aggregates. We also show that MDA-MB-231 cell lysates can "seed" aggregation of the central core domain of recombinant WT p53, corroborating the prion-like behavior of mutant p53. We also noted that this aggregation effect was inhibited by MQ and PRIMA-1. This study provides the first demonstration that PRIMA-1 can rescue amyloid-state p53 mutants, a strategy that could be further explored as a cancer treatment.

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Section: Prima-1 Lowers Amyloid Oligomers Levels In Mutant P53 Cancercontrasting

confidence: 90%

p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells

Rangel

Ferretti

Costa

et al. 2019

Journal of Biological Chemistry

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“…For example PRIMA-1 induced the expression of heat shock protein 90 (Hsp90) in breast cancer cells, restored the p53-Hsp90 interaction and enhanced the translocation of the p53-Hsp90 complex to the nucleus [72]. Recently the ability of PRIMA-1 to induce nucleolar localization and degradation of mutant p53 protein has been demonstrated [73], suggesting the existence of a complex mode of action, likely cell-type specific, that can be independent from the restoration of transactivation functions to mutant p53. Indeed, PRIMA-1 fails to stimulate the DNA binding potential of isolated mutant p53 DBD in vitro [59].…”

Section: Discussionmentioning

confidence: 99%

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

Andreotti¹,

Ciribilli²,

Monti³

et al. 2011

PLoS ONE

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BackgroundThe p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4.Methodology/Principal FindingsGiven the many factors that might influence p53 function, including expression levels, mutations, cofactor proteins and small molecules, we expanded our previously described yeast-based system to provide the opportunity for efficient investigation of their individual and combined impacts in a miniaturized format. The system integrates i) variable expression of p53 proteins under the finely tunable GAL1,10 promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.Conclusions/SignificanceWe found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins.

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“…The second strategy used to re-activate p53, consists of targeting p53 directly using small molecules as PRIMA-1 (stands for "p53 Reactivation and Induction of Massive Apoptosis") and its methylated form PRIMA-1 Met (APR-246) that have the ability to convert mutant and wild-type inactive p53 to an active conformation, restoring DNA binding and transcriptional activity (51,52). PRIMA-1/PRIMA-1 Met alone or in combination with chemotherapy has been shown to have good efficacy against various types of cancers, such as leukemia (53), breast (54,55), thyroid (56), pancreatic (57), ovarian (58), prostate (59), colorectal (60) and non-small lung cancers (61). The safety of APR-246/PRIMA-1 Met has recently been tested in a phase I clinical trial (62) and after positive data obtained from a clinical phase I/II study with APR-246, a global pivotal phase III study in high grade serous ovarian cancer (HGSOC) patients is also intended for PRIMA-1Met.…”

Section: Co-targeting Of Mapk and Pi3k/akt Signaling Pathwaysmentioning

confidence: 99%

New Drug Combination Strategies in Melanoma: Current Status and Future DirectionsNew Drug Combination Strategies in Melanoma: Current Status and Future Directions

Najem

Krayem

Perdrix

et al. 2017

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Abstract. Melanoma is the deadliest form of skinIncidence and mortality rates for melanomas, the most common form of cancer in people aged from 25 to 29, continue to rise faster than any other cancer type. Although melanoma accounts for only a small percentage of skin cancers, it is responsible for the majority of deaths of all skin cancers (1, 2). Increased understanding of the molecular events involved in melanoma development has led to the identification of novel targets and to the development of new targeted agents. Gene alterations identified in melanoma pointed to distinct molecular subsets of tumors with direct implications in therapeutic strategies. Among these, activating BRAF mutations occur in 50-60% of melanomas (V600E substitution represents about 90% of BRAF mutations), NRAS mutations in 20-30% of melanomas (mutually exclusive with BRAF mutation), KIT mutations and/or amplification in 39% of mucosal and 36% of acral melanomas (3, 4). These mutations opened new therapeutic perspectives targeting the MAPK pathway (hyperactivated in 90% of melanomas) with V600E BRAF, MEK or RTK inhibitors (5-7).Vemurafenib and dabrafenib, specific inhibitors of the mutant BRAF (V600E), have been approved by the Food and Drug Administration (FDA) in 2011 and 2013 respectively, for the treatment of patients with unresectable or metastatic melanoma carrying the V600E mutation in BRAF. Furthermore, trametinib a selective inhibitor of MEK1/2 was approved for the same indication in 2013. The approval of these inhibitors was based on improved rates of overall and progression-free survival compared to chemotherapy in phase III clinical trials (6, 8, 9). Moreover, among new MEK inhibitors in clinical development, pimasertib and binimetinib (MEK162) have been recently reported to be particularly promising in the case of patients with mutant NRAS melanoma (10-12). Finally, the results of clinical trials evaluating RTK inhibitors sunitinib and imatinib in patients presenting mutated c-KIT have been published and showed an average response rate of 20% (7, 13).Targeting MAPK pathway in melanoma with MAPK inhibitors has shown clinical benefit. However, the short duration of response and progression-free survival in patients due to resistance or to general toxicity indicate that 5941

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PRIMA-1 cytotoxicity correlates with nucleolar localization and degradation of mutant p53 in breast cancer cells

Cited by 20 publications

References 27 publications

p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells

p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

New Drug Combination Strategies in Melanoma: Current Status and Future DirectionsNew Drug Combination Strategies in Melanoma: Current Status and Future Directions

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