β-Hydroxybutyrate Attenuates Bisphenol-A-Induced Cellular Responses in Ovarian Cancer Cells

Bisphenol A (BPA) is an endocrine-disrupting chemical that is widely known to modulate cancer-related cellular processes, while β-hydroxybutyrate (BHB), a ketone body, has been implicated in regulating cancer cell metabolism and signaling. The interaction between BPA and BHB under glucose-controlled conditions in Ovarian cancer (OC) cells is not well studied. The OC cell line (SKOV-3) was treated with BHB, BPA, or their combination in the presence or absence of glucose. Cell viability and wound-healing ability were assessed using Alamar Blue dye and wound-healing assays, respectively. Also, the expression of estrogen receptors (Erα and ERβ), the apoptotic marker (caspase-3), PIK3CA, AKT1, and epithelial-mesenchymal transition (EMT) markers (CDH1 and CDH2) was monitored using qPCR. Additionally, common genes between BPA, BHB, and OC were checked through online tools such as Swiss Target Prediction and the ChEMBL database for BPA and BHB's target genes, and GeneCards, OMIM, and Comparative Toxicogenomics Database (CTD) were used to detect target genes in OC. Then, a protein-protein Interaction (PPI) Network was constructed from shared genes. Gene Ontology (GO) and KEGG were detected between common genes through the STRING database. BHB (5 mM) treatment significantly inhibited the BPA (1 μM) exposure-induced increase in SKOV-3 cell viability (p < 0.05), under glucose-controlled conditions. The combined treatment of BPA and BHB significantly reduced wound closure compared with the BPA-treated group alone, both in the presence/absence of glucose (p < 0.05). The expression of Erα (ESR1), Caspase-3, PIK3CA, AKT1, and CDH1 was increased in the BPA+BHB-glucose-group while decreased in BPA-treated cells alone. However, CDH2 showed decrease in the BPA+BHB-glucose-group compared with BPA group. According to our bioinformatics analysis, eighteen genes were common between BPA, BHB, and OC. Among these genes, HMGCR, PPARG, HDAC6, and ESR2 were the top four target genes. Activation of cysteine-type endopeptidase activity involved in the apoptotic process was the top GO term, and osteoclast differentiation was detected as the enriched KEGG pathway among the shared genes. These findings suggest that BPA promotes SKOV 3 cell viability and wound-healing ability, while BHB altered BPA-induced cellular responses in a glucose-dependent condition and is linked with changes in estrogen receptor, apoptotic, PI3K/AKT1, and EMT-related gene expression. These results demonstrate that the cellular responses to combined BPA and BHB treatment in OC cells may be affected by metabolic conditions.