JNK inhibitor SP600125 enhances TGF‑β‑induced apoptosis of RBE human cholangiocarcinoma cells in a Smad‑dependent manner

Lin,Youzhi; Zhang,Binhao; Liang,Huifang; Lu,Yulei; Ai,Xi; Zhang,Bixiang; Chen,Xiaoping

doi:10.3892/mmr.2013.1711

JNK inhibitor SP600125 enhances TGF‑β‑induced apoptosis of RBE human cholangiocarcinoma cells in a Smad‑dependent manner

Authors:
- Youzhi Lin
- Binhao Zhang
- Huifang Liang
- Yulei Lu
- Xi Ai
- Bixiang Zhang
- Xiaoping Chen
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Affiliations: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: October 2, 2013 https://doi.org/10.3892/mmr.2013.1711
Pages: 1623-1629

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Abstract

Transforming growth factor β (TGF‑β) signaling is pivotal for the progression of specific types of tumors at certain stages. However, the mechanism by which TGF‑β is regulated by other factors remains unclear. In this study, the involvement of SP600125, an inhibitor of c‑Jun N‑terminal kinase (JNK), in TGF‑β‑induced apoptosis of the RBE human cholangiocarcinoma cell line was investigated. Exogenous TGF‑β1 activated Smad and non‑Smad signaling pathways, including the JNK pathway in RBE cells, and induced apoptosis, which was inhibited by knockdown of Smad4 expression. SP600125 increased the TGF‑β1‑induced phosphorylation of Smad2 and Smad3, which enhanced the TGF‑β1‑induced transcriptional response and apoptosis in RBE cells. The effect of SP600125 on the transcriptional response and apoptosis was reduced by knockdown of Smad4 expression. In addition, TGF‑β1‑induced apoptosis was abrogated using the pan‑caspase inhibitor Z‑VAD‑fmk. SP600125 promoted the TGF‑β1‑induced caspase cleavage, while knockdown of Smad4 expression counteracted this effect. These results indicate that SP600125 enhances TGF‑β‑induced apoptosis of RBE cells through a Smad‑dependent pathway that involves Smad‑dependent caspase activation. SP600125 is hypothesized to be an ideal therapeutic candidate for treating human cholangiocarcinoma.

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