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

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.

BCN057, a Modulator of GSK3β, Induces KRAS G12D Mutant Pancreatic Cancer Cell Death

“…This trend remained the same with a separate study using much higher doses of Oxaliplatin (75 µM), Irinotecan (50 µM) and 5FU (50 µM) with BCN057 remaining at 10 µM with n = 6 (data not shown). This is consistent with the observation of others 28 where GSK-3β has been shown to regulate the sensitivity of MIA-PaCa-2, Pancreatic, and MCF-7 breast cancer cells to Chemotherapeutic Drugs.…”

Effects of the Mutant TP53 Reactivator APR-246 on Therapeutic Sensitivity of Pancreatic Cancer Cells in the Presence and Absence of WT-TP53

“…Dusty Miller (Fred Hutchinson Cancer Center, Seattle, Washington, DC, USA) [ 29 ]. MIA-PaCa-2 and PANC-28 cells containing either WT-TP53 or pLXSN have been previously described [ 30 , 31 , 32 ].…”

“…MIA-PaCa-2 + pLXSN, MIA-PaCa-2 + WT-TP53, PANC-28 + pLXSN, and PANC-28 + WT-TP53 cells were seeded into 96-well cell culture plates (BD Biosciences, Bedford, MA, USA) at a density of 5000 cells/well in 100 μL of phenol red free RPMI-1640 containing 1% FBS. Cell culture plates were incubated for one day to allow cells to adhere to the bottom of each well [ 32 ]. The treatment medium was prepared by performing ten two-fold serial dilutions to create a range of eleven concentrations of the different drugs, signal transduction inhibitors, and nutraceuticals.…”

APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells

“…The sources of the PDAC cell lines and culture conditions have been extensively described previously [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ].…”

“…The sources of vectors encoding WT-TP53 and pLXSN been described previously [ 80 , 81 ]. Retroviral transduction was previously described [ 75 , 82 , 83 , 84 ].…”