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.

Keywords

apoptosis / TGF-β / FoxO3 / casein kinase I-ϵ / hepatocarcinoma

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