Zhou Lixia, Yu Tenghua, Yang Fei, Han Jingjing, Zuo Bin, Huang Lulu, Bai Xia, Jiang Miao, Wu Depei, Chen Suning, Xia Lijun, Ruan Jia, Ruan Changgeng
Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, NHC Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Suzhou, China.
Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
Front Oncol. 2021 Jun 15;11:668617. doi: 10.3389/fonc.2021.668617. eCollection 2021.
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin's B-cell lymphoma with poor prognosis. Despite recent advances, resistance to therapy and relapse remain significant clinical problems. G-protein-coupled estrogen receptor (GPER)-mediated estrogenic rapid signaling is implicated in the development of many cancers. However, its role in MCL is unknown. Here we report that GPER activation with selective agonist G-1 induced cell cycle arrest, DNA damage, mitochondria membrane potential abnormality, and eventually apoptosis of MCL cell lines. We found that G-1 induced DNA damage and apoptosis of MCL cells by promoting the expression of nicotinamide adenine dinucleotide phosphate oxidase and the generation of reactive oxygen species. In addition, G-1 inhibited MCL cell proliferation by inactivation of NF-κB signaling and exhibited anti-tumor functions in MCL xenografted mice. Most significantly, G-1 showed synergistic effect with ibrutinib making it a potential candidate for chemotherapy-free therapies against MCL.
套细胞淋巴瘤（MCL）是一种侵袭性非霍奇金B细胞淋巴瘤，预后较差。尽管近年来取得了进展，但对治疗的耐药性和复发仍然是严重的临床问题。G蛋白偶联雌激素受体（GPER）介导的雌激素快速信号传导与许多癌症的发生发展有关。然而，其在MCL中的作用尚不清楚。在此我们报告，用选择性激动剂G-1激活GPER可诱导MCL细胞系的细胞周期停滞、DNA损伤、线粒体膜电位异常，并最终导致细胞凋亡。我们发现，G-1通过促进烟酰胺腺嘌呤二核苷酸磷酸氧化酶的表达和活性氧的产生，诱导MCL细胞的DNA损伤和凋亡。此外，G-1通过使NF-κB信号失活来抑制MCL细胞增殖，并在MCL异种移植小鼠中表现出抗肿瘤功能。最显著的是，G-1与依鲁替尼显示出协同作用，使其成为一种潜在的无化疗治疗MCL的候选药物。
