Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death
Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death
复制标题
DRD5（多巴胺受体 D5）的激活通过自噬细胞死亡抑制肿瘤生长
DOI：
10.1080/15548627.2017.1328347
复制
发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Wu, Zhe Bao
中科院分区：
文献类型：
--
作者：
Leng, Zhi Gen;Lin, Shao Jian;Wu, Zhe Bao
多巴胺激动剂如溴隐亭和卡麦角林已成功用于治疗垂体泌乳素瘤和其他神经内分泌肿瘤。然而，其治疗机制尚未完全了解。在这项研究中，我们证明了DRD 5（多巴胺受体D5）激动剂是垂体瘤生长的有效抑制剂。我们进一步发现，DRD 5激活增加活性氧（ROS）的产生，抑制MTOR通路，诱导巨自噬/自噬，并导致体外和体内自噬细胞死亡（ACD）。此外，DRD 5蛋白在大多数人垂体腺瘤中高度表达，用DRD 5激动剂SKF 83959处理不同的人垂体瘤细胞培养物导致生长抑制，并且疗效与肿瘤中DRD 5的表达水平相关。此外，我们发现DRD 5在其他人类癌细胞如胶质母细胞瘤、结肠癌和胃癌中表达。这些细胞系中的DRD 5活化抑制其生长，抑制MTOR活性，并诱导自噬。最后，体内SKF 83959也抑制人胃癌细胞在裸鼠中的生长。我们的研究揭示了DRD 5激动剂的肿瘤抑制作用的新机制，并表明DRD 5激动剂作为治疗不同人类肿瘤和癌症的新治疗方法的潜在用途。
ABSTRACT Dopamine agonists such as bromocriptine and cabergoline have been successfully used in the treatment of pituitary prolactinomas and other neuroendocrine tumors. However, their therapeutic mechanisms are not fully understood. In this study we demonstrated that DRD5 (dopamine receptor D5) agonists were potent inhibitors of pituitary tumor growth. We further found that DRD5 activation increased production of reactive oxygen species (ROS), inhibited the MTOR pathway, induced macroautophagy/autophagy, and led to autophagic cell death (ACD) in vitro and in vivo. In addition, DRD5 protein was highly expressed in the majority of human pituitary adenomas, and treatment of different human pituitary tumor cell cultures with the DRD5 agonist SKF83959 resulted in growth suppression, and the efficacy was correlated with the expression levels of DRD5 in the tumors. Furthermore, we found that DRD5 was expressed in other human cancer cells such as glioblastomas, colon cancer, and gastric cancer. DRD5 activation in these cell lines suppressed their growth, inhibited MTOR activity, and induced autophagy. Finally, in vivo SKF83959 also inhibited human gastric cancer cell growth in nude mice. Our studies revealed novel mechanisms for the tumor suppressive effects of DRD5 agonists, and suggested a potential use of DRD5 agonists as a novel therapeutic approach in the treatment of different human tumors and cancers.