1. Department of Medical Oncology, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
2. Key Laboratory of Carcinogenesis and Translational Research, Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China
* These authors contributed equally to this work.
Peritoneal metastasis is the most common pathway for the spread of ovarian cancer and one of the major causes of cancer death. Ovarian cancer cells in ascites prefer to aggregate into the multicellular spheroids (MCS) with an inadequate response to chemotherapy. In this study, gene expression analysis implicated that ovarian cancer MCS had its unique expression pattern and the cell cycle-related pathways were prominently altered in MCS cells compared to the monolayer adherent cells. Flow cytometry and western blots confirmed the cell cycle stagnancy in MCS. Among the cell cycle-related proteins, we found that expression of CDC25A was upregulated in MCS and displayed a time-dependent decrease during the transition from MCS to monolayer adherent cells. Loss-of-function studies showed that CDC25A promoted cisplatin-resistance and paclitaxel-resistance and inhibited the drug-induced apoptosis in ovarian cancer MCS. Mechanically, CDC25A impeded cell cycle progression in MCS cells, enhanced their structure integrity, and maintained upregulation of E-cadherin in MCS cells. Accordingly, addition of NSC95397, a small molecular inhibitor of CDC25A, sensitized the ovarian cancer MCS to chemotherapeutic agents. This provides us a novel strategy for the treatment of ovarian cancer peritoneal metastasis and may help improve the overall survival of ovarian cancer patients.
Keywords: Ovarian Neoplasms, Multicellular Spheroids, CDC25A, Drug Resistance, Cell Cycle, and Molecular Targeted Therapy