Glycogen Synthase Kinase-3β Participates in Nuclear Factor κB–Mediated Gene Transcription and Cell Survival in Pancreatic Cancer Cells

Abstract

Recent studies using glycogen synthase kinase-3B (GSK-3B)-deficient mouse embryonic fibroblasts suggest that GSK-3B positively regulates nuclear factor KB (NFKB)-mediated gene transcription. Because NFKB is suggested to participate in cell proliferation and survival pathways in pancreatic cancer, we investigated the role of GSK-3B in regulating these cellular processes. Herein, we show that pancreatic cancer cells contain a pool of active GSK-3B and that pharmacologic inhibition of GSK-3 kinase activity using small molecule inhibitors or genetic depletion of GSK-3B by RNA interference leads to decreased cancer cell proliferation and survival. Mechanistically, we show that GSK-3B influences NFKBmediated gene transcription at a point distal to the IK kinase complex, as only ectopic expression of the NFKB subunits p65/p50, but not an IK kinase B constitutively active mutant, could rescue the decreased cellular proliferation and survival associated with GSK-3B inhibition. Taken together, our results simultaneously identify a previously unrecognized role for GSK-3B in cancer cell survival and proliferation and suggest GSK-3B as a potential therapeutic target in the treatment of pancreatic cancer. (Cancer Res 2005; 65(6): 2076-81)

Glycogen synthase kinase-3β positively regulates the proliferation of human ovarian cancer cells

“…Tumor growth was measured by tumor diameters with a vernier caliper and by tumor weight. Tumor volume was calculated according to the formula: TV (mm 3 )=d 2 ×D/2, where d and D are the shortest and the longest diameter, respectively [14].…”

“…Recent work in colorectal cancer, pancreatic cancer and hepatocellular carcinoma [2][3][4] demonstrates that glycogen synthase kinase-3β (GSK-3β) is involved in the process of tumorigenesis. Inhibition of the expression and activity of GSK-3β attenuates cell proliferation and causes apoptosis in colorectal and pancreatic cancer cells [2,3].…”

“…Inhibition of the expression and activity of GSK-3β attenuates cell proliferation and causes apoptosis in colorectal and pancreatic cancer cells [2,3]. In contrast, activation of GSK-3β by LY294002 sensitizes hepatoma cells to chemotherapy-induced apoptosis [4].…”

“…However, there are also reports that GSK-3β participates in the NF-κB-mediated gene transcription, which predicts that GSK-3β inactivation would decrease cell proliferation [3,12,13]. Together, these reports prompted us to investigate the role of GSK-3β in ovarian cancer.…”

GSK-3β as a driving force in ovarian cancer

“…Given that overactive β-catenin signaling is involved in many forms of human cancer, this classic mode of GSK-3β action should qualify it as a "tumor suppressor". Intriguingly, however, two recent studies have implicated that GSK-3β may actually play a pro-tumor role in pancreatic and colorectal cancers [2,3]. Since ovarian tumors often exhibit increased expression of GSK-3β, these recent findings prompted Cao et al to examine the potential role of GSK-3β in ovarian cancer cells.…”