Wild-Type p53 Overexpression Inhibits DNA Damage Pathways and Reduces PD-L1 Expression in Prostate Cancer.

Abstract

The DNA damage response (DDR) pathway is crucial in tumor development and metastasis, influencing the tumor microenvironment. This study explores how p53, encoded by TP53, regulates PD-L1 expression in prostate cancer (PCa) from clinical, cellular, and tissue perspectives. Clinical PCa samples were analyzed for PD-L1, PD-1, p53, and PARP1 protein expression. DU145 cells were transfected with plasmids to overexpress wild-type p53 (WT-p53) and PD-L1. Protein and mRNA levels were measured by western blotting and qRT-PCR. DNA damage was assessed by γH2AX staining and comet assays. Cell proliferation was evaluated by colony formation assays, and apoptosis was analyzed by flow cytometry. A mouse tumor model was established to monitor tumor growth. Protein levels, γH2AX, and DNA damage were measured in mouse tumor tissues. Analysis of clinical samples showed a significant negative correlation between p53 and PD-L1/PARP1 levels. In vitro and in vivo experiments confirmed that WT-p53 overexpression reduces γH2AX expression, inhibiting DDR pathway activation. This led to decreased PARP1 and PD-L1 expression, increased apoptosis, and suppressed PCa cell proliferation. This study demonstrates that WT-p53 inhibits the activation of the DDR pathway, thereby leading to the downregulation of PARP1 and PD-L1 protein expression. These findings provide a novel theoretical foundation and potential therapeutic targets for future PCa treatments and research.