Effect of TP53 contact and conformational mutations on cell survival and erythropoiesis of human hematopoietic stem cells in a long term culture model

Salari, Azam; Thomay, Kathrin; Lentes, Jana; Ebersold, Juliane; Hagedorn, Maike; Skawran, Britta; Davenport, Claudia; Schambach, Axel; Schlegelberger, Brigitte; Göhring, Gudrun

doi:10.18632/oncotarget.25581

Cited by 2 publications

(1 citation statement)

References 30 publications

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“…In previous reports,32–34 p53 mutations have been divided into two representative categories: conformational mutations and DNA-contact mutations. Among these mutations, we selected R175H (conformational mutation) and R273H (DNA-contact mutation) respectively, because these two mutations are the most common in each category35 and have different features 36…”

Section: Discussionmentioning

confidence: 99%

Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection

Nishikawa¹,

Menju²,

Takahashi³

et al. 2019

CMAR

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Purpose: The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma. Materials and methods: Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model. Results: Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14–3.85). Conclusion: Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection

Nishikawa¹,

Menju²,

Takahashi³

et al. 2019

CMAR

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TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review)

Tornesello

2024

Int J Mol Med

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The tumour suppressor factor p53 plays an essential role in regulating numerous cellular processes, including the cell cycle, DNA repair, apoptosis, autophagy, cell metabolism and immune response. TP53 is the most commonly mutated gene in human cancers. These mutations are primarily non-synonymous changes that produce mutant p53 proteins characterized by loss of function, a dominant negative effect on p53 tetramerisation and gain of function (GOF). GOF mutations not only disrupt the tumour-suppressive activities of p53 but also endow the mutant proteins with new oncogenic properties. Recent studies analysing different pathogenic features of mutant p53 in cancer-derived cell lines have demonstrated that restoring wild-type p53, rather than removing GOF mutations, reduces cancer cell growth. These findings suggest that therapeutic strategies for reactivating wild-type p53 function in cancer cells may bring a greater benefit than approaches halting mutant p53. This approach could involve the use of small molecules, gene therapy and other methods to re-establish wild-type p53 activity. This review describes the complexity of the biological activities of different p53 mutants and summarizes the current therapeutic approaches to restore p53 function. Contents 1. Introduction 2. Mutations in TP53 gene 3. Therapeutic strategies to target mutant p53 4. Conclusions

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Effect of TP53 contact and conformational mutations on cell survival and erythropoiesis of human hematopoietic stem cells in a long term culture model

Cited by 2 publications

References 30 publications

<p>Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection</p>

<p>Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection</p>

TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review)

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