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- Title
GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals.
- Authors
Abrams, Stephen L.; Akula, Shaw M.; Meher, Akshaya K.; Steelman, Linda S.; Gizak, Agnieszka; Duda, Przemysław; Rakus, Dariusz; Martelli, Alberto M.; Ratti, Stefano; Cocco, Lucio; Montalto, Giuseppe; Cervello, Melchiorre; Ruvolo, Peter; Libra, Massimo; Falzone, Luca; Candido, Saverio; McCubrey, James A.; Yarwood, Stephen
- 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.
- Subjects
GLYCOGEN synthase kinase-3; FUNCTIONAL foods; CANCER cells; BREAST cancer; CANCER chemotherapy; GLYCOLYSIS
- Publication
Cells (2073-4409), 2021, Vol 10, Issue 4, p816
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells10040816