piperidines has been researched along with Bile-Duct-Neoplasms* in 2 studies
2 other study(ies) available for piperidines and Bile-Duct-Neoplasms
| Article | Year |
|---|---|
YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers.
The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity, and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP occupancy defines a subset of enhancers and superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest strategies for intervention. Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Bile Duct Neoplasms; Carcinogenesis; Cell Line, Tumor; Cholangiocarcinoma; Chromatin; Cyclin-Dependent Kinase 9; DNA Polymerase II; Enhancer Elements, Genetic; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Mediator Complex; Mice; Mice, Transgenic; Phosphoproteins; Piperidines; Protein Binding; Signal Transduction; Trans-Activators; Transcription Factors; Transcription, Genetic; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Xenograft Model Antitumor Assays; YAP-Signaling Proteins | 2015 |
Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma.
Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma. Topics: Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Division; Cell Line, Tumor; Cholangiocarcinoma; ErbB Receptors; Female; Gene Amplification; Humans; In Situ Hybridization, Fluorescence; Japan; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidines; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Transplantation, Heterologous; Vascular Endothelial Growth Factor Receptor-2 | 2009 |