Selective metabolic regulations by p53 mutant variants in pancreatic cancer
Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well a...
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Veröffentlicht in: | Journal of experimental & clinical cancer research 2024-11, Vol.43 (1), p.310-17, Article 310 |
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Zusammenfassung: | Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.
To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53
and p53
mutant variants (the mouse equivalents of human p53
and p53
, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell-cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts.
Our investigation revealed that the p53
variant, but not p53
, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53
, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53
induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53
specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53
or p53
does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53
-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells.
Our study elucidates the mutant-specific impact of p53
and p53
on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significa |
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ISSN: | 1756-9966 0392-9078 1756-9966 |
DOI: | 10.1186/s13046-024-03232-3 |