Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Lett. 2019 Sep 10;459:135-144. doi: 10.1016/j.canlet.2019.05.043. Epub 2019 Jun 6.
DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a highly conserved kinase whose hyperactivation is critically involved in a variety of human tumors. The role of DEPTOR playing in pituitary adenoma (PA) is largely unknown. Here, we reported that DEPTOR was downregulated in PA tissues, especially dopamine-resistant prolactinomas. Consistently, overexpression of DEPTOR inhibited pituitary tumor GH3 and MMQ cells proliferation in vitro and in vivo, and sensitized GH3 and MMQ cells to cabergoline (CAB), a dopamine agonist (DA). Conversely, knockdown of DEPTOR promoted GH3 and MMQ cells proliferation, and conferred cells resistance to CAB. Mechanistically, DEPTOR inhibited both mTOR Complex 1 (mTORC1) and 2 (mTORC2) activities in PA cells. In addition, DEPTOR expression level was increased to suppress mTOR kinase activity via decreasing E3 ubiquitin ligase, βTrCP1, in response to CAB. Furthermore, DEPTOR enhanced autophagy-dependent cell death to confer cells sensitivity to CAB. Taken together, our results suggest that DEPTOR may be a potential target for the treatment of PAs.
DEP 结构域含有机械靶标雷帕霉素（mTOR）相互作用蛋白（DEPTOR）是 mTOR 的重要调节剂，mTOR 是一种高度保守的激酶，其过度激活与多种人类肿瘤密切相关。DEPTOR 在垂体腺瘤（PA）中的作用在很大程度上是未知的。在这里，我们报道 DEPTOR 在 PA 组织中下调，特别是多巴胺耐药的泌乳素瘤。一致地，DEPTOR 的过表达抑制了体外和体内垂体瘤 GH3 和 MMQ 细胞的增殖，并使 GH3 和 MMQ 细胞对卡麦角林（CAB）敏感，CAB 是一种多巴胺激动剂（DA）。相反，DEPTOR 的敲低促进了 GH3 和 MMQ 细胞的增殖，并赋予了细胞对 CAB 的耐药性。在机制上，DEPTOR 抑制了 PA 细胞中的 mTOR 复合物 1（mTORC1）和 2（mTORC2）的活性。此外，DEPTOR 的表达水平增加，通过减少 E3 泛素连接酶βTrCP1，以响应 CAB 来抑制 mTOR 激酶活性。此外，DEPTOR 增强了自噬依赖性细胞死亡，使细胞对 CAB 敏感。总之，我们的结果表明 DEPTOR 可能是治疗 PA 的潜在靶点。
