title: Threonine 32 (Thr32) of FoxO3 is critical for TGF-β-induced apoptosis via Bim in hepatocarcinoma cells.
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.
authors.affiliation: 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, zhaoxiangxuan@gmail.com.
authors.forename: Xiangxuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Du
authors.forename: Leya
authors.initials: L
authors.lastname: He
authors.forename: Biyun
authors.initials: B
authors.lastname: Ni
authors.forename: Junbo
authors.initials: J
authors.lastname: Hu
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhu
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D013912:Threonine / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D013912:Threonine