Department of Medicine, Pituitary Center, Cedars SinaiMedical Center, Los Angeles, California 90048, USA.
J Clin Endocrinol Metab. 2009 Nov;94(11):4342-50. doi: 10.1210/jc.2009-1311. Epub 2009 Oct 9.
Pituitary targeted pharmacotherapy for Cushing's disease is challenging and ineffective. Unlike octreotide and lanreotide, the multisomatostatin receptor (SST) analog pasireotide that exhibits SST5 greater than SST2 binding affinity offers potential for treating Cushing's disease. Because corticotroph cells express SST5 more abundantly than SST2, pasireotide likely exerts superior corticotroph action mainly through SST5. However, there is no direct evidence for this assumption, and moreover, the ligand effect on corticotroph SST2 is not known.
We used AtT20 mouse pituitary corticotroph tumor cells stably overexpressing SST2 or SST5 and TtT/GF mouse pituitary folliculostellate cells stably or transiently expressing SST receptors to examine ligand-receptor activation by SST2- and SST5-selective agonists. We show that pasireotide was more potent than either octreotide or somatostatin-14 in mouse corticotroph cells. Pasireotide potency is not affected by SST2 abundance, SST2 antagonist treatment, or octreotide cotreatment in SST2-overexpressing cells. Pasireotide also does not induce SST2 internalization and attenuates octreotide or SRIF14-induced SST2 internalization only at superphysiological dose ranges. In contrast, octreotide attenuates pasireotide potency in SST5-overexpressing cells. Moreover, short exposure to pasireotide causes prolonged inhibition of forskolin or CRH-induced cAMP accumulation, in contrast to somatostatin-14- and SST2-selective agonists that induced postwithdrawal cAMP rebound. Long-term pasireotide signaling effects are enhanced by SST5 overexpression.
The results indicate that SST5 determines short- and long-term enhanced pasireotide action in corticotroph cells, whereas the ligand action on SST2 is negligible.
针对库欣病的靶向垂体药物治疗具有挑战性且效果不佳。不同于奥曲肽和兰瑞肽，具有更高 SST5 结合亲和力的多生长抑素受体（SST）类似物帕瑞肽，为治疗库欣病提供了可能。由于促皮质激素细胞表达的 SST5 比 SST2 更丰富，帕瑞肽可能主要通过 SST5 发挥更好的促皮质激素作用。然而，目前尚没有直接的证据支持这一假设，而且，对于促皮质激素 SST2 的配体作用也并不清楚。
我们使用稳定过表达 SST2 或 SST5 的 AtT20 小鼠垂体促皮质细胞瘤和稳定或瞬时表达 SST 受体的 TtT/GF 小鼠垂体滤泡星状细胞瘤，来检测 SST2 和 SST5 选择性激动剂对受体-配体的激活作用。我们发现，帕瑞肽比奥曲肽或生长抑素-14 对小鼠促皮质激素细胞更有效。在 SST2 过表达细胞中，SST2 丰度、SST2 拮抗剂处理或奥曲肽共处理均不影响帕瑞肽的效力。帕瑞肽也不会诱导 SST2 内化，并且仅在超生理剂量范围内才会减弱奥曲肽或 SRIF14 诱导的 SST2 内化。相比之下，奥曲肽会减弱 SST5 过表达细胞中帕瑞肽的效力。此外，与生长抑素-14 和 SST2 选择性激动剂诱导的停药后 cAMP 反弹相反，短时间暴露于帕瑞肽会导致福司可林或 CRH 诱导的 cAMP 积累持续抑制。长期的帕瑞肽信号转导作用会被 SST5 的过表达增强。
这些结果表明，SST5 决定了帕瑞肽在促皮质激素细胞中的短期和长期增强作用，而配体对 SST2 的作用可以忽略不计。
