Estrogen receptor 1 regulates ovarian cancer cell stemness and ferroptosis through modulation of the canonical RhoA/ROCK signaling pathway

BACKGROUND This study investigated the role of the estrogen receptor 1 (ESR1) in ovarian cancer and its underlying mechanisms. Target genes associated with ovarian cancer, cell stemness, and ferroptosis were identified using DisGeNET and GeneCards databases. AIM To explore the effect of ESR1 on ovarian cancer and its potential molecular mechanism. METHODS ESR1 expression levels in HOSE, SKOV3, A2780, and OVCAR3 cells were assessed using real-time polymerase chain reaction and western blotting. ESR1 knockdown was performed in A2780 cells to evaluate its effects on cell viability, proliferation, apoptosis, aldehyde dehydrogenase activity, cell stemness, ferroptosis, and the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase (ROCK) signaling pathway with or without treatment with CN03 (a Rho activator). RESULTS ESR1 , a gene associated with ovarian cancer, cell stemness, and ferroptosis, was significantly upregulated in ovarian cancer cells and interacted with the RhoA/ROCK signaling pathway. ESR1 knockdown resulted in decreased levels of RhoA, ROCK1, and ROCK2, reduced cell viability and proliferation, and increased apoptosis, all of which were reversed by CN03 treatment. Additionally, si-ESR1 led to decreased aldehyde dehydrogenase activity and cell stemness, reduced expression of octamer-binding transcription factor 4 and Nanog, increased Fe2+ levels, and elevated expression of ferritin heavy chain, ferritin light chain, and transferrin receptor 1. These changes were reversed by CN03 treatment. CONCLUSION ESR1 inhibition regulates cell stemness and ferroptosis in ovarian cancer by modulating the RhoA/ROCK signaling pathway.