Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway

Qi Xiong,Yiming Li,Hongxin Deng,Jia Xu,Jiamei Fu,Yujing Zhang,Gang Shi,Lin Cheng,Na Chen,Shuang Zhang,Fuyi Cheng,Lei Dai,Yong Zhang,Dechao Yu,Huiling Wang,Pengyi Shi,Hantao Zhang,Yang Yang,Jieyan Luo

doi:10.1038/s41388-021-01944-w

Abstract

Dexamethasone (Dex), as a pretreatment agent, is widely used to attenuate the side effects of chemotherapy in breast cancer treatment. However, whether and how Dex affects breast cancer metastasis remain to be furtherly understood. In this study, we established several mouse breast cancer metastatic models to study the effect of Dex in vitro and in vivo. Transwell, Western Blot and RNA interference were applied to study the molecular mechanism of Dex in promoting breast cancer cell migration. Meanwhile, the effect of Dex on lung metastasis of breast cancer in Dex combined with PTX chemotherapy was discussed. Our results confirmed that Dex could promote breast cancer cell metastasis both in vitro and in vivo. Mechanistic studies revealed that this pro-metastatic effect of Dex was mediated by the GR-PI3K-SGK1-CTGF pathway in tumor cells. Ligation of Dex and glucocorticoid receptor (GR) on tumor cells activated the PI3K signaling pathway and upregulated serum glucocorticoid-inducible kinase 1 (SGK1) expression, and then increased the expression of connective tissue growth factor (CTGF) through Nedd4l-Smad2. Moreover, Dex was the leading factor for lung metastasis in a standard regimen for breast cancer treatment with paclitaxel and Dex. Importantly, targeting SGK1 with the inhibitor GSK650394 remarkably reduced lung metastasis in this regimen. Our present data provide new insights into Dex-induced breast cancer metastasis and indicate that SGK1 could be a candidate target for the treatment of breast cancer metastasis.

Highlights

Malignant tumors are characterized by their ability to metastasize, and several discrete steps included cellular adhesion loss, increased migration ability, entry in the circulation, escape from immune surveillance, and eventual colonization of a distant site
Single cytotoxic agent chemotherapy remains the standard regimen for patients with metastatic triple-negative breast cancer [45,46,47]
Recent studies indicated that some breast cancer patients underwent metastasis after receiving treatment, and paclitaxel played a “double-edged sword” role, which conferred both cytotoxic and pro-metastatic effects in cancer cells [4, 5]

Summary

Introduction

Malignant tumors are characterized by their ability to metastasize, and several discrete steps included cellular adhesion loss, increased migration ability, entry in the circulation, escape from immune surveillance, and eventual colonization of a distant site. Our understanding of the potential molecular mechanisms and signaling pathways underlying these phenotypic changes is still fragmentary. Glucocorticoid such as dexamethasone are among the most commonly prescribed immunosuppressive agent widely used in inflammatory diseases [6]. Dex increases glucocorticoid receptor (GR)-mediated reporter activity and cell proliferation while inhibiting apoptosis and cell invasion by suppressing the expression of MMP-2/ MMP9, IL-6 and inducing mesenchymal-to-epithelial transition (MET) in human bladder cancer lines [11]. According to the results of recent study, preoperative dexamethasone treatment was associated with higher rate of distant recurrence in colon cancer patients [12]

Methods

Results

Conclusion