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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Carcinoma, Pancreatic Ductal / drug therapy
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Dose-Response Relationship, Drug
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Drug Synergism
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G1 Phase Cell Cycle Checkpoints / drug effects
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G1 Phase Cell Cycle Checkpoints / genetics
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Gemcitabine
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Gene Expression Regulation, Neoplastic / drug effects*
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Glycogen Synthase Kinase 3 / genetics*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Lithium Chloride / pharmacology*
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis
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Signal Transduction / drug effects*
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Zinc Finger Protein GLI1
Substances
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Antineoplastic Agents
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GLI1 protein, human
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Transcription Factors
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Zinc Finger Protein GLI1
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Deoxycytidine
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Proteasome Endopeptidase Complex
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Lithium Chloride
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Gemcitabine
Grants and funding
This work is supported by the “111 Project” from the Ministry of Education of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.