GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals
Stephen L. Abrams,
Shaw M. Akula,
Akshaya K. Meher,
Linda S. Steelman,
Agnieszka Gizak,
Przemysław Duda,
Dariusz Rakus,
Alberto M. Martelli,
Stefano Ratti,
Lucio Cocco,
Giuseppe Montalto,
Melchiorre Cervello,
Peter Ruvolo,
Massimo Libra,
Luca Falzone,
Saverio Candido,
James A. McCubrey
Affiliations
Stephen L. Abrams
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA
Shaw M. Akula
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA
Akshaya K. Meher
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA
Linda S. Steelman
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA
Agnieszka Gizak
Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wrocław, Poland
Przemysław Duda
Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wrocław, Poland
Dariusz Rakus
Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wrocław, Poland
Alberto M. Martelli
Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy
Stefano Ratti
Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy
Lucio Cocco
Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy
Giuseppe Montalto
Department of Health Promotion, Maternal and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy
Melchiorre Cervello
Institute for Biomedical Research and Innovation, National Research Council (CNR), 90133 Palermo, Italy
Peter Ruvolo
Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
Massimo Libra
Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, 95123 Catania, Italy
Luca Falzone
Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, 95123 Catania, Italy
Saverio Candido
Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, 95123 Catania, Italy
James A. McCubrey
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA
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.