Fatty acid receptor GPR120 promotes breast cancer chemoresistance by upregulating ABC transporters expression and fatty acid synthesisResearch in context
Xue Wang,
Songbing He,
Yuting Gu,
Qiwei Wang,
Xiao Chu,
Min Jin,
Liang Xu,
Qiong Wu,
Qianjun Zhou,
Bei Wang,
Yanyun Zhang,
Hui Wang,
Leizhen Zheng
Affiliations
Xue Wang
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Songbing He
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
Yuting Gu
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qiwei Wang
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Xiao Chu
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Min Jin
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Liang Xu
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qiong Wu
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qianjun Zhou
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Bei Wang
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yanyun Zhang
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author at: Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
Hui Wang
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai 200025, China; Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai 200025, China
Leizhen Zheng
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China; Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.; Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
Background: Chemoresistance is the major cause of neoadjuvant treatment failure in breast cancer patients. Despite recent progress, the mechanism underlying chemoresistance remains to be further defined. Methods: Expression of G protein-coupled receptor 120 (GPR120) was analyzed by immunohistochemistry in the biopsies of primary breast cancer who subsequently underwent preoperative neoadjuvant chemotherapy. In vitro and in vivo loss- and gain-of -function studies were performed to reveal the effects and related mechanism of GPR120 signaling pathway in the chemoresistance of breast cancer cells. Findings: We identified that GPR120, a receptor for long-chain fatty acids, was important for the acquisition of chemoresistance in breast cancer cells. We showed that GPR120 expression was positively associated with clinical response to neoadjuvant chemotherapy in patients. In breast cancer cells, GPR120 enhanced the de novo synthesis of fatty acids that served as GPR120 ligands to activate GPR120 signaling via a feedback mechanism. Upregulated GPR120 signaling rendered cells resistant to epirubicin-induced cell death by upregulating ABC transporters expression and thus decreasing the intracellular accumulation of epirubicin. Akt/NF-κB pathway was responsible for the GPR120-mediated expression of ABC transporters leading to modulation of the concentration of chemotherapeutic drugs in cells. The functional importance of GPR120 in chemoresistance was further validated using epirubicin-treated tumor xenografts, in which we showed that blockade of GPR120 signaling with AH7614 or GPR120-siRNA significantly compromised chemoresistance. Interpretation: Our results highlight that GPR120 might be a promising therapeutic target for breast cancer chemoresistance. Fund: National Natural Science Foundation of China, Ministry of Science and Technology of China, Program of Science and Technology Commission of Shanghai Municipality. Keywords: GPR120, Chemoresistance, ABC transporters, Fatty acid synthesis, Breast cancer
