Bisphenol A exposure confers resistance to cisplatin in ovarian cancer via ERα-dependent DDIT4-mTOR-AKT signaling

Ovarian cancer (OC) is a prevalent gynecological malignancy, with cisplatin (CDDP) serving as the cornerstone of its clinical management. However, the disease progression or recurrence attributable to CDDP resistance has become a major cause of the poor prognosis in OC. Beyond endogenous genetic or epigenetic drivers, the potential contribution of environmental exposure to CDDP resistance in OC remains an enigma. Bisphenol A (BPA), a prototypical environmental endocrine disruptor, has garnered widespread attention due to its pro-carcinogenic effects across various human malignancies. Nevertheless, the latent association between BPA exposure and clinical prognosis of OC has not yet been established. Our current work demonstrated that exposure to environmentally relevant doses of BPA significantly augmented CDDP resistance in human OC cells, which was primarily attributable to AKT-mediated attenuation of DNA damage and apoptosis induced by CDDP. Bioinformatics analysis of a transcriptomic microarray from BPA-exposed OC cells identified DDIT4 as a critical differentially expressed gene involved in BPA-driven CDDP resistance. Mechanistically, estrogen receptor α (ERα), a direct target of BPA dependent activation of a non-canonical DDIT4-mTOR-AKT signaling served as the key molecular event underlying BPA-driven CDDP resistance. Notably, ERα/DDIT4 expression exhibited prominent clinical significance in the prognosis of OC－high ERα/DDIT4 expression was associated with a poor prognosis in patients receiving CDDP treatment, and CDDP treatment failed to hold a tangible clinical benefit in those with high ERα/DDIT4 expression. Overall, our current work advances the understanding of the chemical carcinogenic effects of BPA from a unique perspective of the poor prognosis in OC, and also delivers a novel mechanistic insight into BPA-driven chemoresistance, which might contribute to the identification of promising prognostic biomarkers or chemosensitization targets for environmental exposure-driven OC.