sc-2001 has been researched along with Liver-Neoplasms* in 4 studies
4 other study(ies) available for sc-2001 and Liver-Neoplasms
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RFX1-dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells.
Obatoclax is a small molecule which targets the Bcl-2 family, and is to treat leukemia, lymphoma and lung carcinoma. Previously, an obatoclax analogue, SC-2001, was found to disrupt the protein-protein interactions of the Bcl-2 family and also repress Bcl-XL and Mcl-1 expression via STAT3 inactivation. Here, we report a novel mechanism of autophagy induction by SC-2001 in liver cancer cells. The findings indicate that SC-2001 induced the autophagy marker LC3-II in four hepatocellular carcinoma (HCC) cells. Autophagosomes induced by SC-2001-treated cells were confirmed by electron microscopy. SC-2001 activated SHP-1, dephosphorylated STAT3 and Mcl-1, and subsequently released free beclin 1. Overexpression of STAT3 and Mcl-1 in PLC5 cells attenuated the induction of SC-2001 on autophagy. Abolishment of SHP-1 by a specific inhibitor aboragated the autophagic effects induced by SC-2001. In addition, it was further revealed that RFX-1, a transcription factor of SHP-1, is a critical regulator in SC-2001-mediated autophagy. Downregulation of RFX-1 by si-RNA protected cells from SC-2001-induced autophagy. Importantly, Huh7 tumor-bearing nude mice treated with SC-2001 showed downregulation of Mcl-1 and p-STAT3 protein expression and upregulation of SHP-1, LC3II, and RFX-1 protein expression. In summary, our data suggest that SC-2001 induces autophagic cell death in a RFX1/SHP-1/STAT3/Mcl-1 signaling cascade. Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; DNA-Binding Proteins; Hep G2 Cells; Humans; Liver Neoplasms; Male; Membrane Proteins; Mice, Nude; Microscopy, Electron, Transmission; Microtubule-Associated Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Phagosomes; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyrroles; Regulatory Factor X Transcription Factors; Regulatory Factor X1; RNA Interference; STAT3 Transcription Factor; Transcription Factors; Tumor Burden; Xenograft Model Antitumor Assays | 2014 |
SC-2001 overcomes STAT3-mediated sorafenib resistance through RFX-1/SHP-1 activation in hepatocellular carcinoma.
Hepatocellular carcinoma is the fifth most common solid cancer worldwide. Sorafenib, a small multikinase inhibitor, is the only approved therapy for advanced HCC. The clinical benefit of sorafenib is offset by the acquisition of sorafenib resistance. Understanding of the molecular mechanism of STAT3 overexpression in sorafenib resistance is critical if the clinical benefits of this drug are to be improved. In this study, we explored our hypothesis that loss of RFX-1/SHP-1 and further increase of p-STAT3 as a result of sorafenib treatment induces sorafenib resistance as a cytoprotective response effect, thereby, limiting sorafenib sensitivity and efficiency. We found that knockdown of RFX-1 protected HCC cells against sorafenib-induced cell apoptosis and SHP-1 activity was required for the process. SC-2001, a molecule with similar structure to obatoclax, synergistically suppressed tumor growth when used in combination with sorafenib in vitro and overcame sorafenib resistance through up-regulating RFX-1 and SHP-1 resulting in tumor suppression and mediation of dephosphorylation of STAT3. In addition, sustained sorafenib treatment in HCC led to increased p-STAT3 which was a key mediator of sorafenib sensitivity. The combination of SC-2001 and sorafenib strongly inhibited tumor growth in both wild-type and sorafenib-resistant HCC cell bearing xenograft models. These results demonstrate that inactivation of RFX/SHP-1 induced by sustained sorafenib treatment confers sorafenib resistance to HCC through p-STAT3 up-regulation. These effects can be overcome by SC-2001 through RFX-1/SHP-1 dependent p-STAT3 suppression. In conclusion, the use of SC-2001 in combination with sorafenib may constitute a new strategy for HCC therapy. Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; DNA-Binding Proteins; Drug Resistance, Neoplasm; Drug Synergism; Humans; Liver Neoplasms; Male; Mice; Niacinamide; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyrroles; Regulatory Factor X Transcription Factors; Regulatory Factor X1; Sorafenib; STAT3 Transcription Factor; Transcription Factors; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays | 2014 |
RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells.
Regulatory factor X-1 (RFX-1) is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. Here, we performed several studies to elucidate the roles of RFX-1 in the regulation of SHP-1 in hepatocellular carcinoma (HCC) cells. Overexpression of RFX-1 resulted in the activation of SHP-1 and repressed colony formation of HCC cells. In addition, by a mouse xenograft model, we demonstrated that RFX-1 overexpression also inhibited the tumor growth of HCC cells in vivo, suggesting that RFX-1 is of potential interest for small-molecule-targeted therapy. We also found that SC-2001, a bipyrrole molecule, induced apoptosis in HCC cells through activating RFX-1 expression. SC-2001 induced RFX-1 translocation from the cytosol to nucleus, bound to the SHP-1 promoter, and activated SHP-1 transcription. In a xenograft model, knockdown of RFX-1 reversed the antitumor effect of SC-2001. Notably, SC-2001 is much more potent than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Our study confirmed that RFX-1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for targeted therapy via the activation of the RFX-1/SHP-1 pathway. Topics: Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Hepatocellular; Chromatin Immunoprecipitation; DNA-Binding Proteins; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Liver Neoplasms; Luciferases; Male; Mice; Mice, Nude; Niacinamide; Phenylurea Compounds; Promoter Regions, Genetic; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyrroles; Real-Time Polymerase Chain Reaction; Regulatory Factor X Transcription Factors; Regulatory Factor X1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Sorafenib; STAT3 Transcription Factor; Transcription Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays | 2014 |
A novel obatoclax derivative, SC-2001, induces apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation.
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. Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Indoles; Liver Neoplasms; Mice; Mice, Nude; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyrroles; STAT3 Transcription Factor | 2012 |