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

Protein & Cell 2015年第2期6卷 127-138页

作者： Xiangxuan Zhao Yong Liu Lei Du Leya He Biyun Ni Junbo Hu Dahai Zhu Quan Chen 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 University of Chinese Academy of Sciences Beijing 100049 China Department of Radiology Shengjing Hospital of China Medical University Shenyang 110004 China Cancer Research Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430032 China Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences and School of Basic Medicine of Peking Union Medical College Beijing 100005 China College of Life Science Nankai University Tianjin 300071 China

Transforming growth factor-β （TGF-β） exerts apoptotic effects on various types of malignant ceils, 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-βinduced 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-E）. CKI inhibition by small molecule D4476 could abrogate TGF-β-induced FoxO/Smad acti- vation, 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.

关键词： apoptosis TGF-β FoxO3 casein kinasel-ε hepatocarcinoma

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