ArticleCell cycle (Georgetown, Tex.)2013
Wild-type and mutant p53 mediate cisplatin resistance through interaction and inhibition of active caspase-9.
Article in Cell cycle (Georgetown, Tex.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 67 citations in OpenAlex.
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- Dual Pathways of UBE4B Inhibit Apoptosis in p53-Positive Tumor Cells via CCAR2 Degradation.International journal of molecular sciences · 2026Article
- p53: from understanding its structure to advances in therapeutic targeting.Signal transduction and targeted therapy · 2026Review
- Increased Tumor Necrosis Factor Superfamily Members in Neuroinflammatory Schizophrenia and Bipolar Disorder Midbrains.Biological psychiatry global open science · 2026Article
- Integrative SMR and single cell & spatial analysis reveals the spatial heterogeneity and prognostic value of CASP9-mediated apoptotic pathways in clear cell renal cell carcinoma.Discover oncology · 2025Article
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
- Phenolic Contents, Antioxidant Activities, LCMS Profiles of Mespilus germanica Leaf Extract and Effects on mRNA Transcription Levels of Apoptotic, Autophagic, and Necrotic Genes in MCF7 and A549 Cancer Cell Lines.Cell biochemistry and biophysics · 2024Article
- The Effects of Zinc Oxide Nanoparticles on Antioxidation, Inflammation, Tight Junction Integrity, and Apoptosis in Heat-Stressed Bovine Intestinal Epithelial Cells In Vitro.Biological trace element research · 2024Article
- A Review on Caspases: Key Regulators of Biological Activities and Apoptosis.Molecular neurobiology · 2023Review
- Gain-of-function p53Scientific reports · 2023Article
- Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma.Frontiers in oncology · 2023Article
- GOF Mutant p53 in Cancers: A Therapeutic Challenge.Cancers · 2022Review
- Anticancer Therapeutic Strategies Targeting p53 Aggregation.International journal of molecular sciences · 2022Review
- Activation ofCancers · 2022Article
- Current insights into the regulation of programmed cell death by TP53 mutation in cancer.Frontiers in oncology · 2022Review
- Review
- Control of Oxidative Stress in Cancer Chemoresistance: Spotlight on Nrf2 Role.Antioxidants (Basel, Switzerland) · 2021Review
- Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease.Frontiers in pharmacology · 2021Review
- Brother of regulator of imprinted sites inhibits cisplatin-induced DNA damage in non-small cell lung cancer.Oncology letters · 2020Article
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Authors and funding
9 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The p53 gene has been implicated in many cancers due to its frequent mutations as well as mutations in other genes whose proteins directly affect p53's functions. In addition, high expression of p53 [wild-type (WT) or mutant] has been found in the cytoplasm of many tumor cells, and studies have associated these observations with more aggressive tumors and poor prognosis. Cytoplasmic mis-localization of p53 subsequently reduced its transcriptional activity and this loss-of-function (LOF) was used to explain the lack of response to chemotherapeutic agents. However, this hypothesis seemed inadequate in explaining the apparent selection for tumor cells with high levels of p53 protein, a phenomenon that suggests a gain-of-function (GOF) of these mis-localized p53 proteins. In this study, we explored whether the direct involvement of p53 in the apoptotic response is via regulation of the caspase pathway in the cytoplasm. We demonstrate that p53, when present at high levels in the cytoplasm, has an inhibitory effect on caspase-9. Concurrently, knockdown of endogenous p53 caused an increase in the activity of caspase-9. p53 was found to interact with the p35 fragment of caspase-9, and this interaction inhibits the caspase-9 activity. In a p53-null background, the high-level expression of both exogenous WT and mutant p53 increased the resistance of these cells to cisplatin, and the data showed a correlation between high p53 expression and caspase-9 inhibition. These results suggest the inhibition of caspase-9 as a potential mechanism in evading apoptosis in tumors with high-level p53 expression that is cytoplasmically localized.
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