Timosaponin AIII Inhibits Migration and Invasion Abilities in Human Cervical Cancer Cells through Inactivation of p38 MAPK-Mediated uPA Expression In Vitro and In Vivo

SIMPLE SUMMARY: Cervical cancer is one of the most common cancers in women. High resistance to chemotherapeutic agents and adaptation to radiotherapy in cervical cancer patients can lead to severe mortality. The aim of our study was to assess Timosaponin AIII (TSAIII) as a novel therapeutic approach for cervical cancer. Our findings first revealed that TSAIII suppresses cell migration, cell invasion, p38 activation and uPA expression. The fact that p38 knockdown synergistically contributes to TSAIII-inhibited uPA expression and invasion activity reveals that the p38–uPA axis mediates the anticancer properties of TSAIII. The antimetastatic properties of TSAIII were further confirmed through findings of pulmonary metastasis in immunodeficient mice in vivo and the anticancer stemness property of TSAIII in cervical cancer stem cells (CCSCs) in vitro. ABSTRACT: Cervical cancer is one of the most common gynecologic cancers globally that require novel approaches. Timosaponin AIII (TSAIII) is a steroidal saponin that displays beneficial effects in antitumor activities. However, the effect of TSAIII on human cervical cancer remains unknown. In this study, we found that TSAIII showed no influence on cell viability, cytotoxicity, cell cycle distribution and apoptosis induction in human cervical cancer cells. TSAIII was revealed to have a significant inhibitory effect on cell migration and invasion through the downregulation of invasion-related uPA expression and p38 MAPK activation in both human cervical cancer cells and cervical cancer stem cells (CCSCs), indicating that the p38 MAPK–uPA axis mediated the TSAIII-inhibited capacity of cellular migration and invasion. In a synergistic inhibition assay, a TSAIII plus p38 siRNA cotreatment revealed a greater inhibition of uPA expression, migration and invasion in human cervical cancer cells. In an immunodeficient mouse model, TSAIII significantly inhibited lung metastases from human cervical cancer SiHa cells without TSAIII-induced toxicity. These findings first revealed the inhibitory effects of TSAIII on the progression of human cervical cancer through its downregulation of p38 MAPK–uPA axis activation. Therefore, TSAIII might provide a potential strategy for auxiliary therapy in human cervical cancer.