TP53 gain-of-function mutations and metabolic adaptation in prostate cancer: a comprehensive review

Abstract

The role of Tumor protein 53 (TP53) in prostate cancer management cannot be overstated, as emerging evidence has shown that TP53 mutations are associated with metabolic adaptation, cancer cell proliferation, and resistance to therapy. This review aimed to summarize the role of TP53 gain-of-function mutations in prostate cancer. The ''gain of function'' of TP53 refers to mutations in the TP53 gene that result in the protein product, p53, gaining new or enhanced functions. While p53 is primarily known as a tumor suppressor, mutations in TP53 can sometimes lead to a paradoxical effect where the mutated p53 protein promotes tumor growth rather than inhibiting it. More than one hundred articles were selected for this review according to the exclusion and inclusion criteria. TP53 mutation was found to alter the metabolism of lipids, carbohydrates, and proteins, which gives prostate cancer a unique adaptive character to survive. It was also established that the TP53 gain-of-function mutation promotes cancer cell proliferation by altering the regulation of cell proliferation, metastasis, genomic instability, differentiation, and stemness. Prostate cancer proliferates as a result of the induction of transcription of cyclin A, cyclin B, & CDK1, PI3K/AKT signaling, and ephrin-B2, activation of STAT3 transcription, transcriptional activation of Myc target genes by TP53 gain-of-function mutant. The mutation in TP53 also induces resistance to drugs. The mechanisms of TP53 mutation for chemoresistance are decreased transmembrane activity of influx drug transporters, increased efflux activity, and enhanced drug metabolism, which inactivates the anticancer drugs. This is carried out through the induction of CYP450 enzyme 3A4 expression, Cyclin Dependent Kinase 1, Cyclin B1 (CCNB1), multidrug resistance protein, overexpression of miR-338-3p, and inhibition of Ca²⁺ transfer to the mitochondria. In conclusion, this review will contribute to a better understanding of the significance of the TP53 mutation (gain-of-function) on metabolic adaptations in prostate cancer as a target for therapeutic strategies.

Received on, 24 August 2025

Accepted on, 22 November 2025

Published on, 27 November 2025