Indole-3-propionic acid suppresses prostate cancer by inducing cell cycle arrest and apoptosis associated with p53...

Prostate cancer (PCa) poses a significant health burden worldwide, with castration-resistant progression representing a major therapeutic challenge. While gut microbiota metabolites have been increasingly linked to tumor development, the specific role of indole-3-propionic acid (IPA) in PCa remains unclear. This study explores the direct antitumor effects and molecular mechanisms of IPA in PCa progression.

Using untargeted metabolomics, circulating metabolite profiles were characterized in serum samples from PCa patients and benign prostatic hyperplasia controls. The antitumor effects of IPA on PCa cells were evaluated with in vitro assays, including colony formation, wound healing, transwell migration, and flow cytometry for cell cycle and apoptosis analysis. In vivo efficacy of IPA was tested using a xenograft mouse model. Transcriptome sequencing (RNA-seq) and gene set enrichment analysis identified key biological processes. Western blot and quantitative PCR validated activation of the p53 signaling pathway.

Metabolomic analysis revealed markedly lower IPA levels in PCa patients, particularly in high-grade PCa. In vitro assays showed that IPA treatment effectively reduced PCa cell proliferation, migration, and invasion. In vivo studies with xenograft models demonstrated that IPA significantly slowed tumor growth. RNA-seq and gene set enrichment analysis pointed to cell cycle regulation as the main biological process affected by IPA. Flow cytometry confirmed that IPA caused cell cycle arrest and increased apoptosis in PCa cells. Mechanistic studies indicated that IPA specifically activates the p53-p21-RB signaling axis. Western blot and qPCR confirmed the increased expression of p53 and p21 after IPA treatment.

IPA inhibits PCa cell proliferation, migration, and invasion, while inducing cell cycle arrest and apoptosis concurrent with the activation of the p53 signaling pathway, suggesting its potential as a new therapeutic option for PCa. These findings position IPA not only as a potential prognostic biomarker but also as a promising candidate for microbiota-based metabolic intervention in PCa management.