TCEP flame retardant linked to prostate cancer progression: Integrative analysis and novel biomarker discovery

Tris (2-chloroethyl) phosphate (TCEP) is a widely used organophosphate flame retardant found in consumer products and human tissues. It is listed as a chemical known to cause cancer, but its effects on prostate cancer (PCa) progression remain unexplored. This study investigates the impact of TCEP on prostate tumor aggressiveness through comprehensive in vitro, in vivo, and multi-omics approaches. PCa cell lines (DU-145 and LNCaP) were treated with 1 or 10 μM TCEP to assess changes in migration, invasion, and proliferation. Male mice bearing PCa xenografts received daily intraperitoneal TCEP (100 μg/kg) to evaluate tumor growth and metastatic spread. Proteomic analysis of TCEP-exposed cells was performed to identify dysregulated pathways, followed by integration with patient transcriptomic data (The Cancer Genome Atlas-Prostate Adenocarcinoma, TCGA-PRAD) to derive a prognostic gene signature. Single-cell RNA-seq data (GSE176031) were analyzed to localize the expression of signature genes in tumor microenvironment compartments. Molecular docking simulations were conducted to assess the predicted structural compatibility between TCEP and candidate target proteins. TCEP exposure significantly increased PCa cell migration, invasion, and proliferation in vitro, and accelerated tumor growth and metastasis in vivo compared to controls. Proteomic profiling revealed that TCEP dysregulates pathways involved in cholesterol metabolism, lysosome function, and PPAR signaling. Mapping TCEP-altered proteins to TCGA data identified a four-gene signature (APOE, SPC25, TSPAN1, VGF) associated with shorter biochemical recurrence-free survival (P < 0.05). Single-cell analysis indicated that these genes are predominantly expressed in immune and stromal cells of the tumor microenvironment. Molecular docking simulations suggested potential structural compatibility between TCEP and the four protein targets, supporting possible molecular interactions that require further experimental validation. This study provides the first evidence that exposure to TCEP can drive PCa progression and metastasis. Our multi-faceted findings reveal novel mechanisms linking an environmental contaminant to PCa aggressiveness and uncover a four-gene prognostic biomarker signature, underscoring the impact of environmental toxicants on cancer progression.