GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Cells

卷:10

AlbertoM. Martelli¹  Lucio Cocco¹  Stefano Ratti¹  Giuseppe Montalto²  Peter Ruvolo³  StephenL. Abrams⁴  AkshayaK. Meher⁴  JamesA. McCubrey⁴  ShawM. Akula⁴  LindaS. Steelman⁴  Agnieszka Gizak⁵  Dariusz Rakus⁵  Przemysław Duda⁵  Melchiorre Cervello⁶  Luca Falzone⁷  Saverio Candido⁷  Massimo Libra⁷ 

[1] Department of Biomedical and Neuromotor Sciences, Università di Bologna, 40126 Bologna, Italy;

[2] Department of Health Promotion, Maternal and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy;

[3] Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA;

[4] Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA;

[5] Department of Molecular Physiology and Neurobiology, University of Wrocław, 50-335 Wrocław, Poland;

[6] Institute for Biomedical Research and Innovation, National Research Council (CNR), 90133 Palermo, Italy;

[7] Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, 95123 Catania, Italy;

关键词: GSK-3β;    targeted therapy;    PDAC;    breast cancer;    KRas;    β-catenin;   

DOI  :  10.3390/cells10040816

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown