Abstract
The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB 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-α-induced increase in CCL5, Akt, NF-κB, and c-FLIPL activation and that CCL5 siRNA could inhibit Akt/NF-κB signaling. Moreover, cordycepin negatively regulated the TNF-α-mediated IκB/NF-κB 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-κB 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-κB signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer.
Highlights
Cordycepin, 3′-Deoxyadenosine, is a known polyadenylation inhibitor with various pharmacological activities, such as anti-proliferative, anti-cancer, and antiinflammatory effects[1,2,3,4,5,6,7,8]
Akt activation was downregulated by cordycepin and a significant (p < 0.05) decrease of Akt activation was observed in SKOV-3 cells treated with CCL5 siRNA (Fig. 4b); whereas CCL5 overexpression increased Akt activation in cordycepin-treated SKOV-3 cells (Fig. 4c)
Other studies reported that cordycepin has anti-cancer and anti-metastatic effects, inhibiting the expression of some critical molecules involved in tumor growth and metastasis by blocking Nuclear factor-κB (NF-κB) activation[30, 31]
Summary
Cordycepin, 3′-Deoxyadenosine, is a known polyadenylation inhibitor with various pharmacological activities, such as anti-proliferative, anti-cancer, and antiinflammatory effects[1,2,3,4,5,6,7,8]. Cordycepin is an active small molecule implicated in regulating various physiological functions by immune-activation and presents various properties, including anti-viral, anti-infection, antiinflammatory, anti-aging, anti-cancer properties, and Official journal of the Cell Death Differentiation Association. Akt /protein kinase B (PKB) is a crucial node in diverse signaling pathways essential in both normal cellular physiology, as well as various disease states. Akt signaling controls cell proliferation and anti-apoptosis, cell growth, glucose metabolism, cell migration, and metastasis. Akt functions through its ability to activate many key pro-oncogenic target genes that induce cell growth or antagonize apoptotic pathways. Nuclear factor-κB (NF-κB) comprises a family of transcription factors that regulate the transcription of cytokines, antimicrobial effectors, and genes that control cellular differentiation, growth, and proliferation in cancer stem cells[23]. The NF-κB pathway is overactivated in aggressive ovarian cancer[25]
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