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.
Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China.
EBioMedicine. 2019 Feb;40:251-262. doi: 10.1016/j.ebiom.2018.12.037. Epub 2019 Feb 6.
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.
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.
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.
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.
化疗耐药性是乳腺癌患者新辅助治疗失败的主要原因。尽管最近取得了进展，但化疗耐药性的机制仍有待进一步明确。
采用免疫组织化学法检测原发性乳腺癌患者新辅助化疗前活检组织中 G 蛋白偶联受体 120（GPR120）的表达。通过体外和体内的失活和功能获得研究，揭示 GPR120 信号通路在乳腺癌细胞化疗耐药中的作用及相关机制。
我们发现，长链脂肪酸的受体 GPR120 对于乳腺癌细胞获得化疗耐药性非常重要。我们表明，GPR120 的表达与患者对新辅助化疗的临床反应呈正相关。在乳腺癌细胞中，GPR120 增强了脂肪酸的从头合成，这些脂肪酸作为 GPR120 的配体，通过反馈机制激活 GPR120 信号。上调的 GPR120 信号通过上调 ABC 转运蛋白的表达，从而减少蒽环类药物阿霉素的细胞内积累，使细胞对阿霉素诱导的细胞死亡产生耐药性。Akt/NF-κB 通路负责 GPR120 介导的 ABC 转运蛋白表达，从而调节细胞内化疗药物的浓度。使用阿霉素处理的肿瘤异种移植进一步验证了 GPR120 在化疗耐药中的功能重要性，我们表明，用 AH7614 或 GPR120-siRNA 阻断 GPR120 信号显著削弱了化疗耐药性。
我们的研究结果强调了 GPR120 可能是治疗乳腺癌化疗耐药性的一个有前途的靶点。
国家自然科学基金、中国科学技术部、上海市科学技术委员会项目。
