Glycogen synthase kinase-3β: a novel therapeutic target for pancreatic cancer

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States with a single-digit 5-year survival rate despite advances in understanding the genetics and biology of the disease. Glycogen synthase kinase-3 alpha (GSK-3 alpha) and GSK-3 beta are serine/threonine kinases that localize to the cytoplasm, mitochondria and nucleus. Although they are highly homologous within their kinase domains and phosphorylate an overlapping set of target proteins, genetic studies have shown that GSK-3 beta regulates the activity of several proteins that promote neoplastic transformation. Significantly, GSK-3 beta is progressively overexpressed during PDAC development where it participates in tumor progression, survival and chemoresistance. Thus, GSK-3 beta has become an attractive target for treating PDAC. Areas covered: This review summarizes the mechanisms regulating GSK-3 beta activity, including upstream translational and post-translational regulation, as well as the downstream targets and their functions in PDAC cell growth, metastasis and chemoresistance. Expert opinion: The activity of GSK-3 kinases are considered cell- and context-specific. In PDAC, oncogenic KRas drives the transcriptional expression of the GSK-3 beta gene, which has been shown to regulate cancer cell proliferation and survival, as well as resistance to chemotherapy. Thus, the combination of GSK-3 inhibitors with chemotherapeutic drugs could be a promising strategy for PDAC.