期刊
CELLS
卷 10, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/cells10040816
关键词
GSK-3β targeted therapy; PDAC; breast cancer; KRas; β -catenin; BCL2; chemotherapeutic drugs; nutraceuticals
类别
资金
- East Carolina Univer-sity Grants [111104, 111110-668715-0000]
- US National Institutes of Health [R01-HL146685]
- Fondazione del Monte di Bologna e Ravenna Research
- Fondazione CARISBO Grant
GSK-3 plays diverse roles in pancreatic and breast cancers, altering the levels of GSK-3 can significantly impact cellular sensitivity to drugs and signal transduction inhibitors, which may be influenced by the tumor background.
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-3 beta in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3 beta. Transfection of MIA-PaCa-2 cells with WT-GSK-3 beta increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3 beta often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3 beta and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3 beta reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3 beta 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-3 beta increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3 beta can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.
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