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Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism
Matilda Eriksson1, Gorbatchev Ambroise1, Amanda Tomie Ouchida1
1Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Abstract:
TP53 is one of the most commonly mutated genes in human cancers. Unlike other tumor suppressors that are frequently deleted or acquire loss-of-function mutations, the majority of TP53 mutations in tumors are missense substitutions, which lead to the expression of full-length mutant proteins that accumulate in cancer cells and may confer unique gain-of-function (GOF) activities to promote tumorigenic events. Recently, mutant p53 proteins have been shown to mediate metabolic changes as a novel GOF to promote tumor development. There is a strong rationale that the GOF activities, including alterations in cellular metabolism, might vary between the different p53 mutants. Accordingly, the effect of different mutant p53 proteins on cancer cell metabolism is largely unknown. In this study, we have metabolically profiled several individual frequently occurring p53 mutants in cancers, focusing on glycolytic and mitochondrial oxidative phosphorylation pathways. Our investigation highlights the diversity of different p53 mutants in terms of their effect on metabolism, which might provide a foundation for the development of more effective targeted pharmacological approaches toward variants of mutant p53.
Insights
Mutant TP53 proteins, common in cancer, exhibit diverse gain-of-function activities. This study reveals varied effects of TP53 mutants on cancer cell metabolism, paving the way for targeted therapies.
Area of Science:
- Molecular Biology
- Cancer Research
- Metabolic Engineering
Background:
- TP53 is frequently mutated in human cancers, often via missense substitutions.
- Mutant TP53 proteins can gain novel functions (GOF) promoting tumorigenesis, including metabolic alterations.
- The specific impact of diverse TP53 mutants on cancer cell metabolism remains largely unexplored.
Purpose of the Study:
- To investigate the metabolic profiling of frequently occurring TP53 mutants in cancer.
- To understand the diverse gain-of-function activities of mutant p53 proteins on cellular metabolism.
- To explore potential therapeutic strategies targeting specific TP53 mutant variants.
Main Methods:
- Metabolic profiling of individual, frequently occurring TP53 mutants.
- Focus on key metabolic pathways: glycolysis and mitochondrial oxidative phosphorylation.
- Comparative analysis of metabolic effects across different TP53 mutants.
Main Results:
- Demonstrated significant diversity in the metabolic effects induced by different TP53 mutants.
- Highlighted distinct impacts on glycolytic and oxidative phosphorylation pathways.
- Provided evidence for mutant-specific alterations in cancer cell metabolism.
Conclusions:
- The gain-of-function activities of TP53 mutants are highly variable.
- Different TP53 mutants exert distinct influences on cancer cell metabolism.
- Findings support the development of targeted pharmacological approaches based on specific TP53 mutant profiles.