Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferation

Abstract

GSK3β is a multifunctional serine/threonine kinase that regulates various cellular pathways, depending on its substrates for phosphorylation. It is evident that regulation of Wnt/β-catenin signaling is only one of its diverse functions. Since oncogenic transcription factors (e.g., c-Jun, c-Myc) and proto-oncoproteins (i.e., β-catenin, Gli proteins) are putative GSK3β substrates for phosphorylation-dependent inactivation, it is hypothesized that GSK3β interferes with cellular neoplastic transformation and tumor development, as exemplified by its activity in Wnt/β-catenin signaling. However, only a few studies have addressed its role(s) in human cancer, and these studies have reported differing effects of GSK3β on cancer cells. Using GSK3β deficient mouse embryonic fibroblasts, it was shown that GSK3β plays a crucial role in cell survival mediated by the nuclear factor-kappaB (NF-κB) pathway (Nature 2000; 406:86-90). Interestingly, we have recently shown that the Wnt/β-catenin and NF-κB pathways were co-activated in colorectal cancer by dysregulation in the ubiquitin system (J Natl Cancer Inst 2004; 96:1161-70). Thus, these observations bring forward apparently opposing notions regarding the functions of GSK3β in neoplastic cells on the one hand, removing a neoplastic trigger by phosphorylation-dependent degradation of β-catenin oncoprotein in the ubiquitin system, and on the other, contributing to a cell proliferation and survival pathways by regulating NF-κB. The present study was therefore undertaken to clarify the role of GSK3β in cancer by analyzing expression and activity of this kinase in colon cancer cells and clinical colorectal cancers and by investigating its effects on cancer cells. In colon cancer cell lines and colorectal cancer patients, levels of GSK3β expression and its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of β-catenin oncoprotein in the tumor cells. Inhibition of GSK3β activity by its Ser9 phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3β activity by chemical inhibitors and its expression by RNA interference targeting GSK3β induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3β in tumor cell survival and proliferation and warrant proposing this kinase as a novel and potential therapeutic target in colorectal cancer.

The Pivotal Roles of GSK3β in Glioma Biology

“…More recent studies indicate a role for GSK3 in the control of neoplastic transformation and tumor development (reviewd in Miyashita et al, 2009b). Overexpression and activation of GSK3 was confirmed in various kinds of cancers such as colorectal, stomach, pancreatic, and liver cancers, as well as leukemia and GBM (Shakoori et al, 2005;Shakoori et al, 2007;Wang et al, 2008;Miyashita et al, 2009a;Mai et al, 2009). Previous studies have shown that inhibition of GSK3 suppresses cancer cell proliferation and induces apoptosis Ougolkov et al, 2007).…”

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

“…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].…”

The Role of Glycogen Synthase Kinase 3-β in Immunity and Cell Cycle: Implications in Esophageal Cancer

“…Our unpublished data have also shown that the expression of phosphorylated GSK3 is significantly higher in the tumor tissue of EC than normal tissue. However, other studies indicate that GSK3b is overexpressed in many human malignancies that may offset the observed phospho-inactivation (Ougolkov et al 2006;Shakoori et al 2005). Future work should aim at determining the role of GSK3 in an in vivo setting, under the pressures of the host immune response, and during various stages of the disease since GSK3 activity, like many proteins, could shift drastically during disease progression.…”