RFX1–dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells
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Jung-Chen Su1, Ping-Hui Tseng6, Cheng-Yi Hsu1, Wei-Tien Tai2,3, Jui-Wen Huang5, Ching-Huai Ko5, Mai-Wei Lin5, Chun-Yu Liu1,4, Kuen-Feng Chen2,3 and Chung-Wai Shiau1
1 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
2 Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
3 National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
4 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
5 Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
6 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
Kuen-Feng Chen, email:
Chung-Wai Shiau, email:
Keywords: SHP-1, STAT3, autophagy, RFX1, obatoclax derivative
Received: January 21, 2014 Accepted: June 1, 2014 Published: June 3, 2014
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.
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