A novel obatoclax derivative, SC-2001, induces apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation

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• 作者：Kuen-Feng Chen^b ; ^c ; ¹ ; ^{kfchen1970@ntu.edu.tw} ; Jung-Chen Su^a ; ¹ ; ^{jjjaannee@hotmail.com} ; Chun-Yu Liu^a ; ^e ; ^g ; ^{liuchunyu_tw@yahoo.com.tw} ; Jui-Wen Huang^f ; ^{jwhuang@itir.org.tw} ; Kuei-Chiu Chen^b ; ^c ; ^{ngc2997306@hotmail.com} ; Wei-Lin Chen^a ; ^{claire_407@hotmail.com} ; Wei-Tien Tai^c ; ^d ; ^{aces0125@hotmail.com} ; Chung-Wai Shiau^a ; ^{cwshiau@ym.edu.tw}
• 关键词：HCC ; hepatocellular carcinoma ; STAT3 ; signal transducers and activators of transcription 3 ; SOCS ; suppressor of cytokine signaling ; SHP-1 ; Src homology region 2 domain-containing phosphatase 1 ; PARP ; poly ADP-ribose polymerase ; DMEM ; Dulbecco&rsquo ; s modi
• 刊名：Cancer Letters
• 出版年：2012
• 期刊代码：44_03043835
• 类别：med
• 出版时间：1 August, 2012
• 卷：321
• 期：1
• 页码：27-35
• 文件大小：1158 K

摘要

We investigated the effects of a novel compound, SC-2001, on hepatocellular carcinoma (HCC). SC-2001, which is structurally related to the Mcl-1 inhibitor obatoclax, showed better antitumor effects than obatoclax in HCC cell lines, including HepG2, PLC5 and Huh-7. Like obatoclax, SC-2001 inhibited the protein-protein interactions between Mcl-1 and Bak. However, SC-2001 downregulated the protein levels of Mcl-1 by reducing its transcription whereas obatoclax had no significant effect on Mcl-1 expression. As Mcl-1 is regulated by signal transducers and activators of transcription 3 (STAT3), we found that SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited transcriptional activities of STAT3 in a dose-dependent manner. In addition to Mcl-1, STAT3-regulated proteins, including survivin and cyclin D1, were also repressed by SC-2001. Notably, SC-2001 reduced IL-6-induced STAT3 activation in HepG2 and PLC5 cells. Ectopic expression of STAT3 abolished the prominent apoptotic death in SC-2001-treated PLC5 cells, indicating that STAT3 is indispensable in mediating the effects of SC-2001. Importantly, SC-2001 enhanced the expression of SHP1, a negative regulator of STAT3. Inhibition of SHP-1 by either specific inhibitor or small interference RNA reduced the apoptotic effects of SC-2001, indicating that SHP-1 plays a key role in mediating SC2001-induced cell death. SC-2001 enhanced the activity of SHP-1 in all tested HCC cells including HepG2, PLC5 and Huh-7. Finally, SC-2001 reduced PLC5 tumor growth, downregulated p-STAT3 and upregulated SHP-1 expression and activity in vivo. In conclusion, our results suggest that SC-2001 induces apoptosis in HCC, and that this effect is mediated through SHP-1-dependent STAT3 inactivation.