title: RFX1-dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells.
abstract: 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.
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Jung-Chen
authors: JC
authors: Su
authors: Ping-Hui
authors: PH
authors: Tseng
authors: Cheng-Yi
authors: CY
authors: Hsu
authors: Wei-Tien
authors: WT
authors: Tai
authors: Jui-Wen
authors: JW
authors: Huang
authors: Ching-Huai
authors: CH
authors: Ko
authors: Mai-Wei
authors: MW
authors: Lin
authors: Chun-Yu
authors: CY
authors: Liu
authors: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors: Kuen-Feng
authors: KF
authors: Chen
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Chung-Wai
authors: CW
authors: Shiau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D004268:DNA-Binding Proteins; C477012:MAP1LC3A protein, human; C579095:MCL1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011758:Pyrroles; C000605537:RFX1 protein, human; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; C000605538:Rfx1 protein, mouse; C572884:SC-2001; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6