Department of Drugs Sciences, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100, Pavia, Italy.
Department of Drugs Sciences, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100, Pavia, Italy.
Pharmacol Res. 2019 May;143:17-26. doi: 10.1016/j.phrs.2019.03.008. Epub 2019 Mar 9.
Recent data have demonstrated that triple negative breast cancer (TNBC) with high glucocorticoid receptor (GR) expression are associated to therapy resistance and increased mortality. Given that GR alternative splicing generates mainly GRα, responsible of glucocorticoids action, we investigated its role in the regulation of RACK1 (Receptor for Activated C Kinase 1), a scaffolding protein with a GRE (Glucocorticoid Response Element) site on its promoter and involved in breast cancer cells migration and invasion. We provide the first evidence that GRα transcriptionally regulates RACK1 by a mechanism connected to SRSF3 splicing factor, which promotes GRα, essential for RACK1 transcriptional regulation and consequently for cells migration. We also establish that this mechanism can be positively regulated by cortisol. Hence, our data elucidate RACK1 transcriptional regulation and demonstrate that SRSF3 involvement in cells migration implies its role in controlling different pathways thus highlighting that new players have to be considered in GR-positive TNBC.
最近的数据表明，高糖皮质激素受体（GR）表达的三阴性乳腺癌（TNBC）与治疗耐药和死亡率增加有关。鉴于 GR 的选择性剪接主要产生负责糖皮质激素作用的 GRα，我们研究了它在调节 RACK1（激活蛋白激酶 C 的受体 1）中的作用，RACK1 是一种支架蛋白，其启动子上有一个 GRE（糖皮质激素反应元件）位点，参与乳腺癌细胞的迁移和侵袭。我们首次提供证据表明，GRα 通过与 SRSF3 剪接因子连接的机制转录调节 RACK1，该因子促进对 RACK1 转录调节至关重要的 GRα，从而促进细胞迁移。我们还确定，这种机制可以被皮质醇正向调节。因此，我们的数据阐明了 RACK1 的转录调节，并证明了 SRSF3 参与细胞迁移意味着它在控制不同途径中的作用，从而强调在 GR 阳性 TNBC 中需要考虑新的参与者。
