Low-dose mono(2-ethylhexyl) phthalate promotes ovarian cancer development through PPAR-dependent PI3K/Akt/NF-B pathway

The plasticizer di(2-ethylhexyl) phthalate (DEHP) and its hydrolysate mono(2-ethylhexyl) phthalate (MEHP) aremajor toxicants fromplastics, but their associationwith hormone-dependent cancers has been controversial. We treated the human ovarian cancer cell lines SKOV3 and A2780 with low concentrations of DEHP/MEHP, and found that although no significant effect on cell proliferation was observed, ovarian cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) were promoted by submicromolar MEHP but not DEHP. Next, ovarian cancer patient data from The Cancer Genome Atlas (TCGA) were obtained and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) supported enrichment and Kaplan-Meier survival analyses, which identified PI3K/Akt pathway as a pivotal signaling pathway in ovarian cancer. We found that 500 nM MEHP treatment significantly increased PIK3CA expression, which could be reversed by the knockdownof peroxisome proliferator-activated receptor alpha (PPAR alpha). Silencing PIK3CA significantly suppressed the MEHP-induced migration, invasion and EMT. In addition, we validated that MEHP treatment promoted phosphorylation of Akt and degradation of I kappa B-alpha, thereby activating NF-kappa B and enhancing NF-kappa B nuclear translocation. In nude mice, MEHP exposure significantly promoted themetastasis of ovarian cancer xenografts, which could be suppressed by the treatment of PPAR alpha inhibitor GW6471. Our findings showed that low-dose MEHP promoted ovarian cancer progression through activating PI3K/Akt/NF-kappa B pathway, in a PPAR alpha-dependent manner. (C) 2021 Elsevier B.V. All rights reserved.