Research Papers:

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

Yina Wang, Haiyan Ma, Chongqiang Zhao, Tianshu Liu, Dan Yan, David Jou, Huameng Li, Cuntai Zhang, Jiagao Lü, Chenglong Li, Jiayuh Lin, Sheng Li and Li Lin _

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Oncotarget. 2017; 8:33683-33693. https://doi.org/10.18632/oncotarget.16898

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Yina Wang1,*, Haiyan Ma1,*, Chongqiang Zhao1, Tianshu Liu1, Dan Yan1, David Jou2, Huameng Li3, Cuntai Zhang4, Jiagao Lü1, Chenglong Li3, Jiayuh Lin2, Sheng Li1, Li Lin1

1Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA

3Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA

4Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

*These authors contributed equally to this work

Correspondence to:

Li Lin, email: [email protected], [email protected]

Sheng Li, email: [email protected]

Keywords: raloxifene, GP130, STAT3, liver cancer

Received: September 28, 2016     Accepted: March 28, 2017     Published: April 06, 2017


Background: Interleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear.

Results: Raloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo.

Materials and Methods: The inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode.

Conclusions: Our results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.

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