RRC ID 72607
Author Lin Y, Zhang B, Liang H, Lu Y, Ai X, Zhang B, Chen X.
Title JNK inhibitor SP600125 enhances TGF-β-induced apoptosis of RBE human cholangiocarcinoma cells in a Smad-dependent manner.
Journal Mol Med Rep
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.
Volume 8(6)
Pages 1623-9
Published 2013-12-1
DOI 10.3892/mmr.2013.1711
PMID 24100678
MeSH Anthracenes / pharmacology* Apoptosis / drug effects* Bile Duct Neoplasms / enzymology Bile Duct Neoplasms / pathology* Bile Ducts, Intrahepatic / drug effects Bile Ducts, Intrahepatic / enzymology Bile Ducts, Intrahepatic / pathology Caspases / metabolism Cell Line, Tumor Cholangiocarcinoma / enzymology Cholangiocarcinoma / pathology* Enzyme Activation / drug effects Humans JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors* JNK Mitogen-Activated Protein Kinases / metabolism Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology Signal Transduction / drug effects Smad Proteins / metabolism* Transforming Growth Factor beta / pharmacology*
IF 2.1
Human and Animal Cells RBE(RCB1292)