Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis.

Zheng Zhang,Honglei Kang,Hanfeng Guan,Zhuowei Lei,Feng Li,Honghua Zhang,Jia Wang,Baoguo Mi,Qian Xu,Chao Song,Huiyong Liu,Yunlong Sun

doi:10.1158/1535-7163.mct-18-0783

Abstract

Bone metastasis is a severe complication associated with various carcinomas. It causes debilitating pain and pathologic fractures and dramatically impairs patients' quality of life. Drugs aimed at osteoclast formation significantly reduce the incidence of skeletal complications and are currently the standard treatment for patients with bone metastases. Here, we reported that serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a pivotal role in the formation and function of osteoclasts by regulating the Ca2+ release-activated Ca2+ channel Orai1. We showed that SGK1 inhibition represses osteoclastogenesis in vitro and prevents bone loss in vivo Furthermore, we validated the effect of SGK1 on bone metastasis by using an intracardiac injection model in mice. Inhibition of SGK1 resulted in a significant reduction in bone metastasis. Subsequently, the Oncomine and the OncoLnc database were employed to verify the differential expression and the association with clinical outcome of SGK1 gene in patients with breast cancer. Our data mechanistically demonstrated the regulation of the SGK1 in the process of osteoclastogenesis and revealed SGK1 as a valuable target for curing bone metastasis diseases.

Highlights

Bone is a common target of metastatic spread in solid tumors
We evaluated the expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) during receptor activator of NF-kB ligand (RANKL)-induced osteoclastogenesis by quantitative real-time RT-PCR and immunoblotting
The potential toxicity of GSK650394 was evaluated by measuring the proliferation of bone marrow mononuclear cells (BMM) via the Cell Counting Kit-8 (CCK-8) after treating the cells with different concentrations of GSK650394

Summary

Introduction

Bone is a common target of metastatic spread in solid tumors. Bone metastasis is generally incurable in patients because of limited therapeutic options [1, 2]. During the process of bone metastasis, cancer cells undergo epithelial– mesenchymal transition (EMT), get transported as circulating tumor cells (CTC), and home to target sites [4]. During the formation of bone metastatic lesions, various osteolytic factors aiming at osteoclasts are secreted by tumor cells. Among these factors, macrophage CSF (M-CSF) and RANKL play a central role in this multistep process [8,9,10]. M-CSF upregulates RANK expression on osteoclast precursors and promotes

Methods

Results

Conclusion