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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 TLR3, CDKN1A, and BAX, were significantly downregulated, indicating a transcriptionally inactive p53. Chromatin immunoprecipitation (ChIP) confirmed diminished p53 binding to TLR3 and CDKN1A promoters, while sequencing ruled out TP53 mutations. A bioinformatic analysis revealed elevated TP53 but reduced TLR3 and CDKN1A 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.

Details

Title
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
Author
Pacheco-Castillo, Nancy C 1 ; Gómez-Montalvo Jesús 2   VIAFID ORCID Logo  ; Olivares-Illana Vanesa 3 ; Recillas-Targa Félix 4 ; Tokar, Erik J 5   VIAFID ORCID Logo  ; Eréndira, Avendaño-Vázquez S 2   VIAFID ORCID Logo  ; Escudero-Lourdes, Claudia 1   VIAFID ORCID Logo 

 Laboratorio de Inmunotoxicología, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, Mexico; [email protected] 
 Consorcio de RNA, Laboratorio de Metabolismo de RNA Largos y Medicina Molecular, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico; [email protected] 
 Laboratorio de Interacciones Biomoleculares y Cáncer, Instituto de Física, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, Mexico; [email protected] 
 Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; [email protected] 
 Stem Cell Toxicology Group, Division of Translational Toxicology, National Institute of Environmental Health Science, Durham, NC 27709, USA; [email protected] 
First page
4253
Publication year
2025
Publication date
2025
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3203203585
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.