Methylparaben and propylparaben promote bladder cancer invasion via MMP2 and PPARG modulation.

OBJECTIVE

Parabens, esters of p-hydroxybenzoic acid, are widely utilized as antimicrobial preservatives in consumer products. While increasing evidence implicates parabens in tumor progression across cancers, their role and mechanisms in bladder cancer (BLCA) remain uncharacterized.

METHODS

Methylparaben (MP) and propylparaben (PP) effects on invasion, migration, and proliferation were assessed in BLCA T24 and SW780 cells. The above effects have also been verified through in vivo experiments. Genes linked to MP, PP, and BLCA were curated from public databases. Hub genes were identified through protein-protein interaction (PPI) networks and an optimized prognostic model using 101 machine learning algorithms. Molecular docking (MD) and molecular dynamics simulations (MDS) evaluated hub gene-paraben interactions, followed by functional validation via transfection assays.

RESULTS

MP and PP significantly enhanced BLCA cell invasion (all P < 0.05) without affecting proliferation or migration. It can also promote tumor growth in nude mice (all P < 0.05). Network toxicology and prognostic modeling identified MMP2 and PPARG as key targets for MP and PP, respectively. MD/MDS confirmed stable binding between parabens and their targets. MP upregulated MMP2 expression, while PP downregulated PPARG (all P < 0.05). MMP2 knockdown and PPARG overexpression partly reversed paraben-induced invasion (all P < 0.05).

CONCLUSION

This study reveals that MP and PP promote BLCA invasion via MMP2 and PPARG modulation, providing mechanistic insights into paraben-associated tumorigenesis and underscoring potential public health implications of paraben exposure. These findings have raised concerns about the risk of BLCA caused by low level environmental exposure to parabens, especially among people with impaired detoxification pathways.