PDF(Pubmed)
Abstract：
G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients. Using the clinically applicable GPER1-selective agonist G-1, we demonstrate that the pharmacological activation of GPER1 triggered in vitro anti-MM activity through apoptosis induction, also overcoming the protective effects exerted by bone marrow stromal cells. Noteworthy, G-1 treatment reduced in vivo MM growth in two distinct xenograft models, even bearing bortezomib-resistant MM cells. Mechanistically, G-1 upregulated the miR-29b oncosuppressive network, blunting an established miR-29b-Sp1 feedback loop operative in MM cells. Overall, this study highlights the druggability of GPER1 in MM, providing the first preclinical framework for further development of GPER1 agonists to treat this malignancy.
摘要：
G蛋白偶联雌激素受体1（GPER1）激活正在成为一种有希望的针对几种癌症类型的治疗策略。虽然GPER靶向在实体瘤的背景下已被广泛研究，其对血液系统恶性肿瘤的影响仍有待充分了解。这里,我们显示，与正常供体或恶性前疾病（意义不明的单克隆丙种球蛋白病和闷烧的MM）相比，来自明显多发性骨髓瘤（MM）和浆细胞白血病患者的浆细胞中GPER1mRNA下调；此外，较低的GPER1表达与MM患者的总体生存率较差相关。使用临床适用的GPER1选择性激动剂G-1，我们证明了GPER1的药理激活通过凋亡诱导触发了体外抗MM活性，还克服了骨髓基质细胞的保护作用。值得注意的是,在两种不同的异种移植模型中，G-1治疗降低了体内MM的生长，甚至带有硼替佐米抗性的MM细胞。机械上,G-1上调miR-29b肿瘤抑制网络，钝化在MM细胞中有效的已建立的miR-29b-Sp1反馈回路。总的来说,这项研究强调了GPER1在MM中的可药用性，为进一步开发GPER1激动剂治疗这种恶性肿瘤提供了第一个临床前框架.
