Targeting p53 pathways: mechanisms, structures and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

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GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2023, Volume and Issue: 1878(3), P. 188890 - 188890

Published: March 29, 2023

Language: Английский

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Mutant p53 in cancer: from molecular mechanism to therapeutic modulation

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(11)

Published: Nov. 18, 2022

Abstract TP53 , a crucial tumor suppressor gene, is the most commonly mutated gene in human cancers. Aside from losing its function, mutant p53 (mutp53) often acquires inherent, novel oncogenic functions, which termed “gain-of-function”. Emerging evidence suggests that mutp53 highly associated with advanced malignancies and poor prognosis, makes it target for development of cancer therapies. Herein, we provide summary our knowledge types spectrum The mechanisms accumulation gain-of-function are also summarized. Furthermore, discuss cancers: genetic instability, ferroptosis, microenvironment, stemness. Importantly, role clinic discussed, particularly regard to chemotherapy radiotherapy. Last, emphasis given emerging strategies on how therapy. Thus, this review will contribute better understanding significance as therapeutic strategies.

Language: Английский

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Recent progress in ferroptosis: inducers and inhibitors

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Dec. 29, 2022

Ferroptosis is a new iron-dependent form of programmed cell death characterized by iron accumulation and lipid peroxidation. In recent years, ferroptosis has garnered enormous interest in disease treatment research communities pursuit to reveal the mechanism key targets because closely related pathophysiological processes many diseases. Recent studies have shown some targets, such as glutathione peroxidase 4 (GPX4) System Xc-, several inducers inhibitors been developed regulate these targets. With emergence on made developments. The selection use are very important for work. This paper briefly introduces regulatory metabolic pathway, lists categorizes commonly used recently inhibitors, discusses their medical application. ends with potential future direction ferroptosis.

Language: Английский

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Overcoming cancer chemotherapy resistance by the induction of ferroptosis

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 66, P. 100916 - 100916

Published: Dec. 29, 2022

Language: Английский

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Cuproptosis: p53-regulated metabolic cell death?

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(4), P. 876 - 884

Published: Feb. 8, 2023

Abstract Cuproptosis is a novel type of copper-induced cell death that primarily occurs in cells utilize oxidative phosphorylation as the main metabolic pathway to produce energy. Copper directly associates with lipoylated proteins tricarboxylic acid cycle, leading disulfide-bond-dependent aggregation these proteins, destabilization iron-sulfur cluster and consequent proteotoxic stress. Cancer prefer glycolysis (Warburg effect) for producing intermediate metabolites energy, thereby achieving resistance cuproptosis. Interestingly, tumor suppressor p53 crucial regulator inhibits drives switch towards cancer cells. Additionally, regulates biogenesis clusters copper chelator glutathione, which are two critical components cuproptotic pathway, suggesting this might play role Furthermore, possible roles mutant regulating cuproptosis discussed. In essay, we review recent progress understanding mechanism underlying cuproptosis, revisit regulation glutathione biosynthesis, propose several potential mechanisms wild-type p53-mediated regulation.

Language: Английский

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The roles of ferroptosis in cancer: Tumor suppression, tumor microenvironment, and therapeutic interventions

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(4), P. 513 - 534

Published: April 1, 2024

Language: Английский

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Understanding the complexity of p53 in a new era of tumor suppression

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(6), P. 946 - 967

Published: May 9, 2024

Language: Английский

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The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(9), P. 2756 - 2771

Published: Jan. 1, 2023

Ferroptosis is an iron-driven cell death modality characterized by iron accumulation and excessive lipid peroxidation.Ferroptosis closely related to mitochondrial function, as indicated studies showing that dysfunction damage promote oxidative stress, which in turn induces ferroptosis.Mitochondria play crucial roles cellular homeostasis, abnormalities their morphology function are associated with the development of many diseases.Mitochondria highly dynamic organelles, stability maintained through a series regulatory pathways.Mitochondrial homeostasis dynamically regulated, mainly via key processes such fission, fusion mitophagy; however, prone dysregulation.Mitochondrial fission mitophagy intimately ferroptosis.Therefore, investigations into regulation during ferroptosis important provide better understanding disease.In this paper, we systematically summarized changes ferroptosis, in-depth mechanism underlying corresponding reference for treatment diseases.

Language: Английский

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PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(14), P. 5459 - 5474

Published: Jan. 1, 2022

Background: Bladder cancer (BCa) is a prevalent urologic malignancy that shows poor prognosis.Abnormal metabolism and its key genes play critical role in BCa progression.In this study, the played by PhosphoGlycerol Dehydrogenase (PHGDH), an important molecule of serine metabolism, was investigated with regard to regulation ferroptosis BCa.Methods: The tissues 90 patients were analyzed RNA-sequencing for differential pathways genes.Western blot, qPCR, IHC used determine PHGDH expression cell lines (in vitro) patient vivo).R software analyze expression, prognosis, PHGDH+SLC7A11 score.The biological functions examined through organoids, vitro vivo experiments.C11 probes, electron microscopy, inhibitors/ inducers detect cellular levels.Protein profiling, co-IP, RIP assays screen proteins might bind PHGDH.PHGDH-targeted inhibitor NCT-502 evaluate effect on cells.Results: highly expressed BCa.Knock-down promoted ferroptosis, while decreased proliferation cells.Additionally, knock-down downregulated SLC7A11.Co-IP mass spectrometry experiments indicate binds PCBP2, RNA-binding protein, inhibits ubiquitination degradation.PCBP2 turn stabilizes SLC7A11 mRNA increases expression.NCT-502, inhibitor, promotes tumor progression BCa.The PHGDH+ score significantly correlated prognosis.Conclusions: To conclude, PHGDH, via interaction upregulates expression.This malignant BCA.The results study indicated could serve as therapeutic strategy BCa.

Language: Английский

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