Iron-induced cellular senescence promotes migration of ovarian cancer spheroids through the CCL26/CCR3 axis

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer. Cellular migration and invasion contribute to the metastasis of cancer cells. The mechanism of metastasis of epithelial ovarian cancer is not fully understood. In this study, we detected cellular senescence-related characteristics in ovarian cancer spheroids derived from ascites of patients with high grade serous ovarian carcinoma (HGSOC), and in ovarian cancer cell lines under suspension conditions. We then performed in vitro experiments to elucidate the molecular mechanism how cellular senescence increased the motility of ovarian cancer spheroids. Epithelial ovarian cancer spheroids derived from HGSOC cell lines or patients’ ascites all showed increased SA-β-galactosidase activity and iron-loaded lipofuscin accumulation. Senescence enhanced the migration of ovarian cancer spheroids through the CCL26/CCR3 axis. CCR3 antagonist inhibited the migration of ovarian cancer spheroids through downregulating the expression of mesenchymal markers. Accumulation of iron-loaded lipofuscin in lysosomes inhibits autophagic flux, resulting in generation of reactive oxygen species (ROS), leading to increased protein levels of CCL26 and vimentin, and migration of ovarian cancer spheroids. Our findings may provide a novel molecular target for the treatment of epithelial ovarian cancer.