https://scholars.lib.ntu.edu.tw/handle/123456789/368285
Title: | A novel obatoclax derivative, SC-2001, induces apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation | Authors: | Kuen-Feng Chen | Keywords: | HCC; Obatoclax; SC-2001; SHP-1; STAT3 | Issue Date: | 2012 | Journal Volume: | 321 | Journal Issue: | 1 | Start page/Pages: | 27-35 | Source: | Cancer Letters | Abstract: | 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. ? 2012. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84860331447&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/368285 |
DOI: | 10.1016/j.canlet.2012.03.023 | SDG/Keyword: | antineoplastic agent; cyclin D1; interleukin 6; obatoclax; protein Bak; protein bcl xl; protein mcl 1; protein tyrosine phosphatase SHP 1; sc 2001; STAT3 protein; survivin; unclassified drug; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer cell culture; cancer inhibition; cell strain HepG2; cell viability; concentration response; controlled study; drug efficacy; drug mechanism; drug potency; drug structure; enzyme activity; human; human cell; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; protein phosphorylation; protein protein interaction; transcription termination; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Liver Neoplasms; Mice; Mice, Nude; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyrroles; STAT3 Transcription Factor |
Appears in Collections: | 醫學系 |
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