Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway

The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-kappa B signaling is significantly activated by CCL5. However, the role of NE-kappa B inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NE-kappa B activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NE-kappa B signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents INF-alpha-induced increase in CCL5, Akt, NE-kappa B, and c-FLIPL activation and that CCL5 siRNA could inhibit Akt/NF-kappa B signaling. Moreover, cordycepin negatively regulated the INF-a-mediated IKB/NE-kappa B pathway and c-FLIPL activation to promote JNK phosphorylation, resulting in caspase-3 activation and apoptosis. Also, we show that c-FLIPL is rapidly lost in NE-kappa B activation-deficient. siRNA mediated c-FLIP inhibition increased INK. SP600125, a selective JNK inhibitor, downregulated p-JNK expression in cordycepin-treated SKOV-3 cells, leading to suppression of cordycepin-induced apoptosis. Thus, these results indicate that cordycepin inhibits CCL5-mediated Akt/NF-kappa B signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer.