Bazedoxifene Suppresses the Growth of Osteosarcoma Cells by Inhibiting IL-6 and IL-11/GP130 Signaling Pathway

Author:

Wu Xiaojuan12,Cao Yang3,Xiao Hui4,Feng Jiexiong1,Lin Jiayuh25

Affiliation:

1. Department of Pediatric Surgery, Tongji Hospital

2. The Research Institute at Nationwide Children’s Hospital, The Ohio State University

3. Department of Hematology & Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China

4. The Ohio State University Comprehensive Cancer Center, Columbus, OH

5. Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD

Abstract

Osteosarcoma is the most common primary bone tumor. Using the multiple ligands simultaneous docking method, we found that bazedoxifene could bind to the GP130 D1 domain. We then demonstrated that bazedoxifene can decrease cell viability and cell migration of osteosarcoma cells by inhibiting interleukin 6 (IL-6) and IL-11/GP130 signaling. Consistently, treatment with IL-6 or IL-11 antibody or knockdown of GP130 by siRNA silenced the activation of STAT3, ERK, and AKT. Similarly, recombinant IL-6 and IL-11 proteins antagonized the inhibitory effect of bazedoxifene on osteosarcoma cells. Finally, the combinational treatment of temsirolimus and bazedoxifene synergistically suppressed osteosarcoma development in vitro and in vivo. Our findings suggest that bazedoxifene directly prompts the deactivation of GP130 and inhibits the osteosarcoma progression in vitro and in vivo. Therefore, bazedoxifene could be effectively applied as a therapeutic drug for human osteosarcoma in the future.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Oncology,Hematology,Pediatrics, Perinatology and Child Health

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