Cordycepin promotes apoptosis in renal carcinoma cells by activating the MKK7-JNK signaling pathway through inhibition of c-FLIPL expression
- Authors
- Hwang, In-Hu; Oh, Seung Yoon; Jang, Hyun-Jin; Jo, Eunbi; Joo, Jong Cheon; Lee, Kyung-Bok; Yoo, Hwa-Seung; Lee, Mi Young; Park, Soo Jung; Jang, Ik-Soon
- Issue Date
- 18-10월-2017
- Publisher
- PUBLIC LIBRARY SCIENCE
- Citation
- PLOS ONE, v.12, no.10
- Indexed
- SCIE
SCOPUS
- Journal Title
- PLOS ONE
- Volume
- 12
- Number
- 10
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/81882
- DOI
- 10.1371/journal.pone.0186489
- ISSN
- 1932-6203
- Abstract
- Cellular FLICE inhibitory protein (c-FLIP) is a key anti-apoptotic regulator that associates with the signaling complex downstream of NF-kappa B, negatively interfering with apoptotic signaling. The role of c-FLIP downregulation by negative regulation of NF-kappa B signaling during apoptosis is poorly understood. Here, we demonstrate that NF-kappa B-mediated c-FLIPL negatively regulates the JNK signaling pathway, and that cordycepin treatment of human renal cancer cells leads to apoptosis induction through c-FLIPL inhibition. TNF-alpha-induced inflammatory microenvironments stimulated NF-kappa B signaling and the c-FLIP long form (c-FLIPL) in TK-10 cells. Specifically, cordycepin inhibited TNF-alpha-mediated NF-kappa B activation, which induced renal cancer cell apoptosis. Cordycepin downregulated GADD45B and c-FLIPL, but upregulated MKK7 and phospho-JNK, by preventing nuclear mobilization of NF-kappa B. Furthermore, siRNA-mediated knockdown of GADD45B in cordycepin-treated TK-10 cells considerably increased MKK7 compared to cordycepin alone. siRNA-mediated knockdown of cFLIP(L) prevented TNF-a-induced JNK inactivation, whereas c-FLIPL overexpression inhibited cordycepin-mediated JNK activation. The JNK inhibitor SP600125 strongly inhibited Bax expression. In nude mice, cordycepin significantly decreased tumor volume. Taken together, the results indicate that cordycepin inhibits TNF-a-mediated NF-kappa B/GADD45B signaling, which activates the MKK7-JNK signaling pathway through inhibition of c-FLIPL expression, thus inducing TK-10 cell apoptosis.
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