Abstract
Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.
Keywords:
BCL2; GSK-3β; KRas; PDAC; breast cancer; chemotherapeutic drugs; nutraceuticals; targeted therapy; β-catenin.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / enzymology
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Adenocarcinoma / pathology
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Adenylate Kinase / metabolism
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Berberine / pharmacology
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Berberine / therapeutic use
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Biphenyl Compounds / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / 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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Deoxycytidine / therapeutic use
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Diabetes Mellitus / drug therapy
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Dietary Supplements*
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Disease Progression
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Doxorubicin / pharmacology
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Doxorubicin / therapeutic use
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Female
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Fluorouracil / pharmacology
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Fluorouracil / therapeutic use
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Gemcitabine
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Glycogen Synthase Kinase 3 beta / metabolism*
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Glycolysis / drug effects
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Humans
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Inhibitory Concentration 50
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MCF-7 Cells
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Malaria / drug therapy
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Metformin / pharmacology
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Metformin / therapeutic use
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Molecular Targeted Therapy*
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Neoplasm Metastasis
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Nitrophenols / pharmacology
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / pathology
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Signal Transduction / drug effects
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Sulfonamides / pharmacology
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Thiadiazoles / pharmacology
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Thiadiazoles / therapeutic use
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Tumor Stem Cell Assay
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / metabolism
Substances
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ABT-737
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Antineoplastic Agents
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Biphenyl Compounds
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Nitrophenols
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Piperazines
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Protein Kinase Inhibitors
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Sulfonamides
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Thiadiazoles
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bcl-X Protein
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Berberine
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Deoxycytidine
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Doxorubicin
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Metformin
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Glycogen Synthase Kinase 3 beta
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Adenylate Kinase
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tideglusib
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Fluorouracil
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Gemcitabine