Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for PRL-secreting pitui-tary tumors but are poorly effective in non-functioning pituitary neuroendocrine tumors (NF-PitNET). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin2-dependent mechanism in mouse striatum. The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement. We found that DRD2 agonist BIM53097 induced a reduction of p- AKT /total-AKT ratio in MMQ (-32.8±17.6%, p<0.001 vs basal) and in a subset (n=15/41,36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase of p-AKT. The ability of BIM53097 to reduce p-AKT correlated to its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097 and nearly all subgroup 2 NF-PitNETs were resistant. β-arrestin 2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs. In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth. In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs responsiveness to treatment with dopamine agonists.


中文翻译：

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β-arrestin 2 是多巴胺受体 2 型对垂体肿瘤 AKT 磷酸化和细胞增殖的抑制作用所必需的。

多巴胺受体 2 型 (DRD2) 激动剂是分泌 PRL 的垂体肿瘤的首选治疗方法，但在无功能垂体神经内分泌肿瘤 (NF-PitNET) 中效果不佳。DRD2 降低了泌乳素细胞中的 AKT 磷酸化，但在 NF-PitNETs 中没有可用的数据。DRD2 对 AKT 的影响是由小鼠纹状体中的 β-arrestin2 依赖性机制介导的。本研究的目的是研究 DRD2 对人原代培养的 NF-PitNET 细胞和大鼠肿瘤泌乳素细胞 MMQ 中 AKT 磷酸化和细胞增殖的影响，并测试 β-arrestin 2 的参与。我们发现 DRD2 激动剂 BIM53097 在 MMQ（-32.8±17.6%，p<0.001 vs 基础）和一部分 NF- PitNETs（子组 1）。在剩余的 NF-PitNETs（子组 2）中，BIM53097 诱导 p-AKT 增加。BIM53097 降低 p-AKT 的能力与其抗有丝分裂作用相关，因为大多数亚组 1 NF-PitNET 对 BIM53097 有反应，并且几乎所有亚组 2 NF-PitNET 都具有抗性。β-arrestin 2 在 MMQ 和 80% 的亚组 1 NF-PitNET 中表达，而在 77% 的亚组 2 NF-PitNET 中检测不到。在 MMQ 中，β-arrestin 2 沉默阻止了 DRD2 对 p-AKT 和细胞增殖的抑制作用。因此，亚组 2 NF-PitNETs 中的 β-arrestin 2 转染赋予 BIM53097 抑制 p-AKT 和细胞生长的能力。总之，我们证明了 β-arrestin 2 是 DRD2 对 MMQ 和 NF-PitNET 中 AKT 磷酸化和细胞增殖的抑制作用所必需的，