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.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a family of kinases consisting of GSK-3α and GSK-3β
The effects of WT-GSK-3β, KD-GSK-3β, and pLXSN on the sensitivity to MIA-PaCa-2 cells to chemotherapeutic drugs were used to treat PDAC are presented in Figures 2 and 3, and Table 1
As in the case of chemotherapeutics used for pancreatic cancer treatment, introduction of WT-GSK-3β into MIA-PaCa-2 cells resulted in an increase of the inhibitory concentration of 50% (IC50) values, i.e., decrease of sensitivity, of the cells to all the tested compounds
Summary
50 to docetaxel, CHIR99021, and SB415286, 1.9-, 3.1, and 3.1-fold, respectively 18, of chemosensitivity, we investigated the effects of combination of the GSK-3 inhibitor tideglusib with low concentrations of docetaxel, SB415286, metformin, and berberine on MCF3.13. Of chemosensitivity, we investigated the effects of combination of the GSK-3 inhibitor tideglusib with low concentrations of docetaxel, SB415286, metformin, and berberine on MCF-7 + pLXSN, MCF-7 + WT-GSK-3β, and MCF-7 + KD-GSK-3β cells (Figures 19–22 and Table 3). As an alternative approach to examine the roles that GSK-3β may play in regulation of chemosensitivity, we investigated the effects of combination of the GSK-3 inhibitor tideglusib with low concentrations of docetaxel, SB415286, metformin, and berberine on MCF7 + pLXSN, MCF-7 + WT-GSK-3β, and MCF-7 + KD-GSK-3β cells
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