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

Zhen Yang Cui, Soo Jung Park, Eunbi Jo, In Hu Hwang, Kyung Bok Lee, Sung Woo Kim, Dae Joon Kim, Jong Chun Joo, Seok Hoon Hong, Min-Goo Lee, Ik Soon Jang

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Article number62
JournalCell Death Discovery
Volume4
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Ovarian Neoplasms
Apoptosis
Caspases
Caspase 3
Small Interfering RNA
Chemokine CCL5
cordycepin
Up-Regulation
Down-Regulation
Phosphorylation
Neoplasms

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway. / Cui, Zhen Yang; Park, Soo Jung; Jo, Eunbi; Hwang, In Hu; Lee, Kyung Bok; Kim, Sung Woo; Kim, Dae Joon; Joo, Jong Chun; Hong, Seok Hoon; Lee, Min-Goo; Jang, Ik Soon.

In: Cell Death Discovery, Vol. 4, No. 1, 62, 01.12.2018.

Research output: Contribution to journalArticle

Cui, ZY, Park, SJ, Jo, E, Hwang, IH, Lee, KB, Kim, SW, Kim, DJ, Joo, JC, Hong, SH, Lee, M-G & Jang, IS 2018, 'Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway', Cell Death Discovery, vol. 4, no. 1, 62. https://doi.org/10.1038/s41420-018-0063-4
Cui, Zhen Yang ; Park, Soo Jung ; Jo, Eunbi ; Hwang, In Hu ; Lee, Kyung Bok ; Kim, Sung Woo ; Kim, Dae Joon ; Joo, Jong Chun ; Hong, Seok Hoon ; Lee, Min-Goo ; Jang, Ik Soon. / Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway. In: Cell Death Discovery. 2018 ; Vol. 4, No. 1.
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AU - Kim, Sung Woo

AU - Kim, Dae Joon

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AU - Hong, Seok Hoon

AU - Lee, Min-Goo

AU - Jang, Ik Soon

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AB - 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.

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