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The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2017 Jun 30; Vol. 292 (26), pp. 10813-10823. Date of Electronic Publication: 2017 May 15. - Publication Year :
- 2017
-
Abstract
- In 95% of patients with pancreatic ductal adenocarcinoma, recurrence is observed following chemotherapy. Findings from several studies have indicated that cancer stem cells (CSCs) are resistant to anticancer agents and may be involved in cancer recurrence and metastasis. The CD44 protein is a major CSC marker, and CD44 also plays an indispensable role in the CSC properties in several cancers, including pancreatic cancer; however, no clinical approach exists to inhibit CD44 activity. Here, we have performed knock-in/knockdown experiments, and we demonstrate that the forkhead box O3 (FOXO3)/liver kinase B1 (LKB1)/AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ co-activator-1β (PGC-1β)/pyruvate dehydrogenase-A1 pathway is essential for CD44 expression and CSC properties. We observed that patients exhibiting high pyruvate dehydrogenase-A1 expression have a poor prognosis. Systemic PGC-1β knock-out mice are fertile and viable and do not exhibit an overt phenotype under normal conditions. This suggests that cGMP induction and PGC-1β inhibition represent potential strategies for treating patients with pancreatic ductal adenocarcinoma.<br /> (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Animals
Biomarkers, Tumor genetics
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal pathology
Carrier Proteins genetics
Cell Line, Tumor
Female
Forkhead Box Protein O3 genetics
Humans
Male
Mice, Knockout
Neoplasm Proteins genetics
Neoplastic Stem Cells
Pancreatic Neoplasms genetics
Pancreatic Neoplasms pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
RNA-Binding Proteins
Biomarkers, Tumor metabolism
Carcinoma, Pancreatic Ductal metabolism
Carrier Proteins metabolism
Forkhead Box Protein O3 metabolism
Neoplasm Proteins metabolism
Pancreatic Neoplasms metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 292
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28507102
- Full Text :
- https://doi.org/10.1074/jbc.M116.772111