RESEARCH ARTICLE

Threonine 32 (Thr32) of FoxO3 is critical for TGF-β-induced apoptosis via Bim in hepatocarcinoma cells

  • Xiangxuan Zhao , 1,2,3 ,
  • Yong Liu 1,2 ,
  • Lei Du 1,2 ,
  • Leya He 4 ,
  • Biyun Ni 1,2 ,
  • Junbo Hu 4 ,
  • Dahai Zhu 5 ,
  • Quan Chen , 1,2,6
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  • 1. The Joint Laboratory of Apoptosis and Cancer Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China
  • 3. Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
  • 4. Cancer Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China
  • 5. Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences and School of Basic Medicine of Peking Union Medical College, Beijing 100005, China
  • 6. College of Life Science, Nankai University, Tianjin 300071, China

Received date: 01 Sep 2014

Accepted date: 30 Oct 2014

Published date: 05 Feb 2015

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Transforming growth factor- β (TGF- β) exerts apoptotic effects on various types of malignant cells, including liver cancer cells. However, the precise mechanisms by which TGF- β induces apoptosis remain poorly known. In the present study, we have showed that threonine 32 (Thr32) residue of FoxO3 is critical for TGF- β to induce apoptosis via Bim in hepatocarcinoma Hep3B cells. Our data demonstrated that TGF- β induced FoxO3 activation through specific de-phosphorylation at Thr32. TGF- β-activated FoxO3 cooperated with Smad2/3 to mediate Bim up-regulation and apoptosis. FoxO3 (de)phosphorylation at Thr32 was regulated by casein kinase I- ϵ (CKI- ϵ). CKI inhibition by small molecule D4476 could abrogate TGF- β-induced FoxO/Smad activation, reverse Bim up-regulation, and block the sequential apoptosis. More importantly, the deregulated levels of CKI- ϵ and p32FoxO3 were found in human malignant liver tissues. Taken together, our findings suggest that there might be a CKI-FoxO/Smad-Bim engine in which Thr32 of FoxO3 is pivotal for TGF- β-induced apoptosis, making it a potential therapeutic target for liver cancer treatment.

Cite this article

Xiangxuan Zhao , Yong Liu , Lei Du , Leya He , Biyun Ni , Junbo Hu , Dahai Zhu , Quan Chen . Threonine 32 (Thr32) of FoxO3 is critical for TGF-β-induced apoptosis via Bim in hepatocarcinoma cells[J]. Protein & Cell, 2015 , 6(2) : 127 -138 . DOI: 10.1007/s13238-014-0121-5

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