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

ABSTRACT: The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-?B signaling is significantly activated by CCL5. However, the role of NF-?B inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-?B activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-?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 TNF-?-induced increase in CCL5, Akt, NF-?B, and c-FLIPL activation and that CCL5 siRNA could inhibit Akt/NF-?B signaling. Moreover, cordycepin negatively regulated the TNF-?-mediated I?B/NF-?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 NF-?B activation-deficient. siRNA mediated c-FLIP inhibition increased JNK. 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-?B signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer.

SUBMITTER: Cui ZY 

PROVIDER: S-EPMC5966410 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature