Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 26, Pages 10813-10823Publisher
ELSEVIER
DOI: 10.1074/jbc.M116.772111
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Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI [22228002, 15H02448]
- JSPS KAKENHI [15K18821]
- Grants-in-Aid for Scientific Research [15H02448, 15K18821] Funding Source: KAKEN
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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-gamma co-activator-1 beta (PGC-1 beta)/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-1 beta knock-out mice are fertile and viable and do not exhibit an overt phenotype under normal conditions. This suggests that cGMP induction and PGC-1 beta inhibition represent potential strategies for treating patients with pancreatic ductal adenocarcinoma.
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