PDF(Pubmed)
Abstract：
Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAA β3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAA β3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAA β3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAA β3 subunit decreases TNBC proliferation and migration. In addition, GABAA β3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAA receptors containing the β3 subunit can be further developed as a potential novel target for the treatment of TNBC.
摘要：
三阴性乳腺癌（TNBC）以其异质性和侵袭性发作而闻名。对激素疗法和免疫疗法的无反应性和化学疗法的毒性解释了TNBC的有限治疗选择。离子通道已经成为癌症治疗的可能治疗候选药物，但对配体如何门控离子通道知之甚少，具体来说,GABAA型配体门控离子通道受体（GABAAR），影响癌症的发病机制。我们的结果表明，GABAAβ3亚基在TNBC细胞系中的表达水平高于非致瘤细胞，因此有助于通过敲低GABAAβ3亚基限制GABAAR是降低TNBC细胞增殖和迁移的潜在策略。我们采用药理学和遗传学方法来研究GABAAβ3亚基在TNBC增殖中的作用。迁移,和细胞周期进程。结果表明，GABAAβ3亚基的药理拮抗作用或基因敲除作用可降低TNBC的增殖和迁移。此外,GABAAβ3亚基敲低通过减少细胞周期蛋白D1和增加p21表达导致TNBC细胞系中的细胞周期停滞。我们的发现表明，含有β3亚基的膜结合GABAA受体可以进一步发展为治疗TNBC的潜在新靶标。
