1. Lithium inhibits tumorigenic potential of PDA cells through targeting hedgehog-GLI signaling pathway.
- Author
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Peng Z, Ji Z, Mei F, Lu M, Ou Y, and Cheng X
- Subjects
- Apoptosis drug effects, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, Cell Proliferation drug effects, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Dose-Response Relationship, Drug, Drug Synergism, G1 Phase Cell Cycle Checkpoints drug effects, G1 Phase Cell Cycle Checkpoints genetics, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Humans, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Proteasome Endopeptidase Complex drug effects, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Proteolysis, Transcription Factors metabolism, Zinc Finger Protein GLI1, Gemcitabine, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic drug effects, Glycogen Synthase Kinase 3 genetics, Lithium Chloride pharmacology, Signal Transduction drug effects, Transcription Factors genetics
- Abstract
Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA) and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β) that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.
- Published
- 2013
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