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

Abstract

Esophageal cancer (EC) is one of the most aggressive gastrointestinal malignancies, possessing an insidious onset and a poor prognosis. Numerous transcription factors and inflammatory mediators have been reported to play a pivotal role in the initiation and progression of this cancer. However, the specifics of the signaling network responsible for said factors, especially which elements are the critical regulators, are still being elucidated. Glycogen synthesis kinases 3 (GSK3)b was originally regarded as a kinase regulating glucose metabolism. Accumulating evidence demonstrated that it also played an essential role in a variety of cellular processes including proliferation, differentiation, inflammation, motility, and survival by regulating various transcription factors such as c-Jun, AP-1, b-catenin, CREB, and NF-jB. Aberrant regulation of GSK3b has been shown to promote cell growth in some cancers, while suppressing it in others, and thus may play an important role in the development of EC. This review will discuss our current understanding of GSK3b signaling, and its control of the expression and activation of various transcription factors that mediate the inflammatory response. We will also explore some of the known mediators of EC progression, and based on current literature, elucidate the potential roles and implications of GSK3 in this disease.

Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer

“…Esophageal cancer is the eighth most frequent tumor and sixth leading cause of cancer death worldwide. Whereas the majority of cases occur in Asia, particularly in central China, recent data suggest that the frequency of new cases is rising in Western Europe and the USA [ 9 , 10 ]. Two major histological subtypes of esophageal cancer have been identified including squamous cell carcinoma (ESCC), which is more common in developing countries, and adenocarcinoma, which is more common in developed nations [ 11 ].…”

Inhibition of glycogen synthase kinase 3 beta (GSK3β) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity

“…The annual incidence rate of esophageal cancer is 3/10 5 person‐years in the US white population and reaches 1000/10 5 person‐years in some areas of China . The median survival time of patients with inoperable cancer is estimated to be only 13‐29 months, and the 5‐year survival rate of EC patients is only 10‐20% after radiotherapy or esophagotomy . These epidemiologic results reflect the low efficiency of current treatments, underscoring the need for a deeper understanding of the molecular mechanisms underlying this disease as well as for new therapeutic strategies for its treatment.…”

“…Phosphorylation at Serine 9 of GSK3β leads to a structural change and decreases its activity . PI3K activation results in Akt phosphorylation and the subsequent phosphorylation/inactivation of GSK3β, which has been demonstrated to suppress the production of pro‐inflammatory cytokines including IL‐12, TNFα, IL‐1β, IL‐6, IFNγ, and IL‐17, while it concurrently promotes the production of IL‐10, IL‐1Ra, and IFNβ by immune cells . Moreover, GSK3β is also involved in Wnt signaling pathways.…”

“…16 PI3K activation results in Akt phosphorylation and the subsequent phosphorylation/inactivation of GSK3β, which has been demonstrated to suppress the production of pro-inflammatory cytokines including IL-12, TNFα, IL-1β, IL-6, IFNγ, and IL-17, while it concurrently promotes the production of IL-10, IL-1Ra, and IFNβ by immune cells. 10,18 Moreover, GSK3β is also involved in Wnt signaling pathways. GSK3β inhibition leads to the accumulation of β-catenin in the nucleus, which enhances the progression of most cancers.…”

Expression of serum- and glucocorticoid-regulated kinase 1 and its association with clinicopathological factors and the survival of patients with adenocarcinoma of the esophagogastric junction

“…Firstly, it has been previously demonstrated that SGK1 is associated with the progression of inflammation (22–24), and inflammation per se has been demonstrated to be associated with the development of multiple types of cancer (25,26). A previous study demonstrated that active SGK1 decreases the production of pro-inflammatory cytokines, such as tumor necrosis factor, interleukin (IL)-12, and IL-1 (23).…”