TY - JOUR
T1 - Glycogen synthase kinase-3β
T2 - a novel therapeutic target for pancreatic cancer
AU - Ding, Li
AU - Billadeau, Daniel D.
N1 - Funding Information:
This work was supported by a Fellowship Grant from the Eagles 5th District Cancer Telethon Funds for Cancer Research and the Mayo Clinic Center for Biomedical Discovery to L Ding and an NCI supported Pancreatic Cancer SPORE grant [CA102701] to DD Billadeau.
Publisher Copyright:
© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/5/3
Y1 - 2020/5/3
N2 - 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-3α (GSK-3α) and GSK-3β 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-3β regulates the activity of several proteins that promote neoplastic transformation. Significantly, GSK-3β is progressively overexpressed during PDAC development where it participates in tumor progression, survival and chemoresistance. Thus, GSK-3β has become an attractive target for treating PDAC. Areas covered: This review summarizes the mechanisms regulating GSK-3β 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-3β 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.
AB - 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-3α (GSK-3α) and GSK-3β 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-3β regulates the activity of several proteins that promote neoplastic transformation. Significantly, GSK-3β is progressively overexpressed during PDAC development where it participates in tumor progression, survival and chemoresistance. Thus, GSK-3β has become an attractive target for treating PDAC. Areas covered: This review summarizes the mechanisms regulating GSK-3β 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-3β 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.
KW - GSK-3
KW - GSK-3 inhibitors
KW - KRas
KW - pancreatic cancer
KW - pancreatic ductal adenocarcinoma
KW - targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=85082411303&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082411303&partnerID=8YFLogxK
U2 - 10.1080/14728222.2020.1743681
DO - 10.1080/14728222.2020.1743681
M3 - Review article
C2 - 32178549
AN - SCOPUS:85082411303
SN - 1472-8222
VL - 24
SP - 417
EP - 426
JO - Expert opinion on therapeutic targets
JF - Expert opinion on therapeutic targets
IS - 5
ER -