β-Arrestin 1 and 2 and G Protein-Coupled Receptor Kinase 2 Expression in Pituitary Adenomas: Role in the Regulation of Response to Somatostatin Analogue Treatment in Patients With Acromegaly
β-Arrestin 1 and 2 and G Protein-Coupled Receptor Kinase 2 Expression in Pituitary Adenomas: Role in the Regulation of Response to Somatostatin Analogue Treatment in Patients With Acromegaly
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DOI：
10.1210/en.2013-1672
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发表时间：
2013-12-01
期刊：
影响因子：
4.8
通讯作者：
Hofland, Leo J.
中科院分区：
文献类型：
--
作者：
Gatto, Federico;Feelders, Richard;Hofland, Leo J.
最近的体外研究强调了G蛋白偶联受体激酶（GRK） 2和β -抑制素在驱动生长抑素受体（SSTR）脱敏和运输中的重要作用。我们的目的是表征GRK2和β -抑制素在不同垂体腺瘤中的表达，并研究它们在gh分泌腺瘤（GHomas）中对生长抑素类似物（SSA）治疗的反应中的潜在作用。我们评估了41个垂体腺瘤（31个垂体腺瘤，6个非功能性垂体腺瘤[nfpa]和4个泌乳素瘤[PRLomas]）中多种SSTRs、GRK2、β -抑制素1和β -抑制素2的mRNA表达。在GHomas组中，mRNA数据与急性奥曲肽试验的体内反应以及SSA在培养的原代细胞中的gh降低作用相关。3种腺瘤组织型中β -阻滞蛋白1的表达均较低。但与nfpa相比，其在GHomas和PRLomas中的表达明显降低（P < 0.01）。GRK2在PRLomas和nfpa中的表达高于GHomas （P < 0.05）。在GHoma组中，GRK2表达与β - arestin 1呈负相关（P < 0.05），与β - arestin 2呈正相关（P < 0.0001）。SSA治疗不影响GRK2和β -抑制素在GHomas或培养的大鼠垂体瘤GH3细胞中的表达。值得注意的是，在体外对奥曲肽治疗有反应的肿瘤中，β -抑制素1显著降低（P < 0.05），而GRK2和SSTR亚型2显著升高（P < 0.05）。同样，β - arestin 1水平与急性奥曲肽试验的体内反应呈负相关（P = .001），而GRK2和SSTR亚型2表达呈正相关（P < .05）。总之，我们首次在具有代表性的垂体腺瘤中表征了GRK2、β -抑制素1和β -抑制素2的表达。β -阻滞素1和GRK2似乎在SSA治疗期间调节GH分泌中起作用。
Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK) 2 and beta-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and beta-arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH-secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, beta-arrestin 1, and beta-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]). Within the GHomas group, mRNA data were correlated with the in vivo response to an acute octreotide test and with the GH-lowering effect of SSA in cultured primary cells. beta-Arrestin 1 expression was low in all 3 adenoma histotypes. However, its expression was significantly lower in GHomas and PRLomas, compared with NFPAs (P < .01). GRK2 expression was higher in PRLomas and NFPAs compared with GHomas (P < .05). In the GHoma group, GRK2 expression was inversely correlated to beta-arrestin 1 (P < .05) and positively correlated to beta-arrestin 2 (P < .0001). SSA treatment did not affect GRK2 and beta-arrestin expression in GHomas or in cultured rat pituitary tumor GH3 cells. Noteworthy, beta-arrestin 1 was significantly lower (P < .05) in tumors responsive to octreotide treatment in vitro, whereas GRK2 and SSTR subtype 2 were significantly higher (P < .05). Likewise, beta-arrestin 1 levels were inversely correlated with the in vivo response to acute octreotide test (P = .001), whereas GRK2 and SSTR subtype 2 expression were positively correlated (P < .05). In conclusion, for the first time, we characterized GRK2, beta-arrestin 1, and beta-arrestin 2 expression in a representative number of pituitary adenomas. beta-Arrestin 1 and GRK2 seem to have a role in modulating GH secretion during SSA treatment.