JNK inhibitor SP600125 enhances TGF-β-induced apoptosis of RBE human cholangiocarcinoma cells in a Smad-dependent manner.
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.
['Lin|Youzhi|Y|', 'Zhang|Binhao|B|', 'Liang|Huifang|H|', 'Lu|Yulei|Y|', 'Ai|Xi|X|', 'Zhang|Bixiang|B|', 'Chen|Xiaoping|X|']
D000873:Anthracenes D017209:Apoptosis D001650:Bile Duct Neoplasms D001653:Bile Ducts, Intrahepatic D020169:Caspases D045744:Cell Line, Tumor D018281:Cholangiocarcinoma D004789:Enzyme Activation D006801:Humans D048031:JNK Mitogen-Activated Protein Kinases D010766:Phosphorylation D047428:Protein Kinase Inhibitors D015398:Signal Transduction D051785:Smad Proteins D016212:Transforming Growth Factor beta
SP600125 apoptosis cholangiocarcinoma Smad transforming  growth  factor  β