Cordyceps militaris Extract Inhibits the NF-KB pathway and Induces Apoptosis through MKK7-JNK Signaling Activation in TK-10 Human Renal Cell Carcinoma

Abstract

The ubiquitous transcription factor, NF-KB, has been reported to inhibit apoptosis and induce drug resistance in cancer cells. Cordyceps militaris extract (CME) is involved in the regulation of the NF-KB signaling pathway. However, the detailed role of CME in the suppression of the NF-KB signaling pathway is unclear. We found that CME dose-dependently inhibited tumor necrosis factor-alpha (TNF-alpha)-induced NF-KB activation in TK-10 human renal cell carcinoma. CME prevented NF-KB from translocating to the nucleus, which resulted in the downregulation of GADD45B, upregulation of MKK7, and phosphorylation of JNK (p-JNK). The increased activation of Bax led to pronounced CME-induced apoptosis, which occurred through caspase-3. Furthermore, the siRNA-mediated knockdown of GADD45B inhibited MKK7 expression, whereas the siRNA-mediated inhibition of MKK7 downregulated p-JNK and the JNK inhibitor, SP600125, inhibited Bax expression. Thus, these results indicated that CME inhibited the activation of GADD45B via the inhibition of NF-KB activation, which upregulated the MKK7-JNK signaling pathway to induce apoptosis in TK-10 cells. Thus, this study reveals a novel anticancer function of CME.