(101) Environmental Endocrine Disruptor Benzophenone Drives Ovarian Cancer Progression via GPR30/PI3K/mTOR Pathway and HoxA9 Hypermethylation

Environmental Endocrine Disruptor Benzophenone Drives Ovarian Cancer Progression via GPR30/PI3K/mTOR Pathway and HoxA9 Hypermethylation 

Inyoung KANG¹; Jaewang LEE^1,2

¹ Department of Senior Healthcare, Biopharmaceutical Sciences, Eulji University, Uijeongbu, 11759, Korea

² Department of Biomedical Laboratory Sciences, Eulji University, Seongnam 13135, Korea

Abstract Text:

Benzophenone (BP), a commonly used photo-initiator and former UV filter, is classified as an endocrine-disrupting chemical (EDC) by regulatory authorities due to its potential interference with the endocrine system. However, its role in ovarian cancer progression and the underlying mechanisms remain largely unexplored. In this study, we investigated the oncogenic potential of BP in ovarian cancer using the COV434 cell line, a representative granulosa cell tumor model. BP exposure at concentrations of 1, 10, and 100 µM induced nuclear translocation of estrogen receptor alpha (ERα), indicating its estrogenic activity. BP treatment also significantly enhanced COV434 cell proliferation, migration, and colony formation capacity in two-dimensional cultures. To better mimic the tumor microenvironment, we established three-dimensional (3D) spheroid cultures of COV434 cells. BP-treated spheroids exhibited increased invasiveness and a larger spreading area compared to untreated controls, indicating that BP promotes aggressive cancer phenotypes in 3D culture systems. Mechanistic studies revealed that BP activated the GPR30/PI3K/mTOR signaling pathway, as evidenced by increased expression of related genes. Additionally, BP exposure led to hypermethylation of the HoxA9 gene, accompanied by upregulation of DNA methyltransferases (DNMTs), suggesting epigenetic regulation as a potential mechanism contributing to the observed oncogenic effects. Collectively, these findings demonstrate that BP enhances ovarian cancer progression through both activation of non-classical estrogen signaling via the GPR30/PI3K/mTOR pathway and epigenetic modifications such as HoxA9 hypermethylation. These data suggest that environmental exposure to BP may pose a risk factor for ovarian cancer progression and highlight the need for further evaluation of EDCs in female reproductive cancers.