Inorganic Arsenic Induces Elevated p53 Levels with Altered Functionality Impacting the Expression of Toll-like Receptor 3 and Other Target Genes in Immortalized Prostate Epithelial Cells

Prostate cancer (PCa) is a major global health concern, particularly in advanced stages where chemotherapy resistance and androgen-independent tumor growth reduce survival rates to below 30%. Toll-like receptor 3 (TLR3), regulated by tumor suppressor p53, is a promising therapeutic target due to its role in tumor cell apoptosis. However, chronic exposure to inorganic arsenic (iAs), a known carcinogen, has been linked to PCa progression and reduced TLR3 expression and activation by polyinosinic/polycytidylic acid (Poly(I/C)), a synthetic ligand used in PCa immunotherapy. Here, we demonstrate that chronic sodium arsenite (NaAsO) exposure increases p53 transcript and protein levels in immortalized prostate epithelial cells. Despite this, key p53 target genes, including <i>TLR3</i>, <i>CDKN1A</i>, and <i>BAX</i>, were significantly downregulated, indicating a transcriptionally inactive p53. Chromatin immunoprecipitation (ChIP) confirmed diminished p53 binding to <i>TLR3</i> and <i>CDKN1A</i> promoters, while sequencing ruled out <i>TP53</i> mutations. A bioinformatic analysis revealed elevated <i>TP53</i> but reduced <i>TLR3</i> and <i>CDKN1A</i> in prostate adenocarcinoma, suggesting that iAs-induced oxidative stress disrupts p53 function. These findings reveal a novel mechanism by which iAs promotes PCa progression through impaired p53 activity, highlighting the need to explore post-translational and epigenetic factors affecting p53. Restoring p53 transcriptional activity may offer a therapeutic strategy for PCa patients exposed to NaAsO.