The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma

Motofumi Kumazoe, Mika Takai, Shun Hiroi, Chieri Takeuchi, Mai Kadomatsu, Takashi Nojiri, Hiroaki Onda, Jaehoon Bae, Yuhui Huang, Kanako Takamatsu, Shuya Yamashita, Kenji Kangawa, Hirofumi Tachibana

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10813-10823
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number26
DOIs
Publication statusPublished - Jun 30 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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