TY - JOUR
T1 - The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma
AU - Kumazoe, Motofumi
AU - Takai, Mika
AU - Hiroi, Shun
AU - Takeuchi, Chieri
AU - Kadomatsu, Mai
AU - Nojiri, Takashi
AU - Onda, Hiroaki
AU - Bae, Jaehoon
AU - Huang, Yuhui
AU - Takamatsu, Kanako
AU - Yamashita, Shuya
AU - Kangawa, Kenji
AU - Tachibana, Hirofumi
N1 - Funding Information:
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grants 22228002 and 15H02448 (to H. T.), a grant-in-aid for JSPS fellows (to M. Kumazoe) (PD), and JSPS KAKENHI Grant 15K18821. The authors declare that they have no conflicts of interest with the contents of this article. We appreciate technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University, and the Center for Accelerator and Beam Applied Science, Kyushu University. We thank Takeshi Iwasaki (Kyushu University, Faculty of Medicine) for helpful advice on bioinformatics analysis.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/6/30
Y1 - 2017/6/30
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M116.772111
DO - 10.1074/jbc.M116.772111
M3 - Article
C2 - 28507102
AN - SCOPUS:85021682258
VL - 292
SP - 10813
EP - 10823
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 26
ER -
