G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Mantle Cell Lymphoma Growth in Preclinical Models.

Lixia Zhou,Bin Zuo,Xia Bai,Depei Wu,Jia Ruan,Miao Jiang,Suning Chen,Lijun Xia,Tenghua Yu,Changgeng Ruan,Jingjing Han,Lulu Huang,Fei Yang

doi:10.3389/fonc.2021.668617

Abstract

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.

Highlights

Mantle cell lymphoma (MCL) is a rare and aggressive form of B-cell lymphoma, characterized by the hallmark translocation [11;14] (q13; q32) that results in overexpression of cyclin D1 and cell proliferation [1]
We explored the effects of G-protein-coupled estrogen receptor (GPER) agonist G-1 on MCL and investigated the mechanism of its action
We found that G-1 up-regulated NADPH oxidases expression in MCL cells

Summary

Introduction

Mantle cell lymphoma (MCL) is a rare and aggressive form of B-cell lymphoma, characterized by the hallmark translocation [11;14] (q13; q32) that results in overexpression of cyclin D1 and cell proliferation [1]. Additional genomic alterations, which are involved in cell cycle, DNA damage, signal transduction, and apoptosis [2, 3], are found to contribute to MCL progression and Abbrevations: MCL, Mantle cell lymphoma; GPER, G-protein-coupled estrogen receptor; BTK, Bruton’s tyrosine kinase; EGFR, epidermal growth factor receptor; ROS, reactive oxygen species; g-H2A.X, phospho-H2A.X; NOX, NADPH oxidase; NF-kB, nuclear factor kappa-B; NAC, N-Acetyl-L-cysteine; H2DCFDA, 2′,7′-dichlorofluorescin diacetate; DSB, doublestrand break. G-1 Inhibits MCL Growth resistance to conventional chemotherapy [4, 5]. Recent advances in cytostatic drugs, including the development of immunomodulatory imide drugs such as lenalidomide and the Bruton’s tyrosine kinase (BTK) inhibitor such as ibrutinib, have established chemo-free regimes as a promising new direction of MCL therapy [5,6,7]. There is a need to identify new targeted therapeutic options for MCL

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Results

Conclusion