School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Endocrinology. 2022 May 1;163(5). doi: 10.1210/endocr/bqac031.
Previous studies investigating the effects of blocking the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in prostate cancer found no effects of the growth hormone receptor (GHR) antagonist, pegvisomant, on the growth of grafted human prostate cancer cells in vivo. However, human GHR is not activated by mouse GH, so direct actions of GH on prostate cancer cells were not evaluated in this context. The present study addresses the species specificity of GH-GHR activity by investigating GH actions in prostate cancer cell lines derived from a mouse Pten-deletion model. In vitro cell growth was stimulated by GH and reduced by pegvisomant. These in vitro GH effects were mediated at least in part by the activation of JAK2 and STAT5. When Pten-mutant cells were grown as xenografts in mice, pegvisomant treatment dramatically reduced xenograft size, and this was accompanied by decreased proliferation and increased apoptosis. RNA sequencing of xenografts identified 1765 genes upregulated and 953 genes downregulated in response to pegvisomant, including many genes previously implicated as cancer drivers. Further evaluation of a selected subset of these genes via quantitative reverse transcription-polymerase chain reaction determined that some genes exhibited similar regulation by pegvisomant in prostate cancer cells whether treatment was in vivo or in vitro, indicating direct regulation by GH via GHR activation in prostate cancer cells, whereas other genes responded to pegvisomant only in vivo, suggesting indirect regulation by pegvisomant effects on the host endocrine environment. Similar results were observed for a prostate cancer cell line derived from the mouse transgenic adenocarcinoma of the mouse prostate (TRAMP) model.
先前的研究调查了阻断生长激素（GH）/胰岛素样生长因子-1（IGF-1）轴对前列腺癌的影响，发现生长激素受体（GHR）拮抗剂培维索孟对体内移植的人前列腺癌细胞的生长没有影响。然而，人类 GHR 不能被鼠 GH 激活，因此在这种情况下，没有评估 GH 对前列腺癌细胞的直接作用。本研究通过研究源自鼠 Pten 缺失模型的前列腺癌细胞系中 GH 的作用，解决了 GH-GHR 活性的种属特异性问题。GH 可刺激体外细胞生长，培维索孟可减少体外细胞生长。这些 GH 的体外作用至少部分是通过 JAK2 和 STAT5 的激活介导的。当 Pten 突变细胞作为异种移植物在小鼠中生长时，培维索孟治疗可显著减小异种移植物的大小，这伴随着增殖减少和凋亡增加。对异种移植物进行 RNA 测序鉴定出 1765 个上调基因和 953 个下调基因，这些基因与之前被认为是癌症驱动基因的基因有关。通过定量逆转录-聚合酶链反应对这些基因的一个选定子集进行进一步评估，确定了一些基因在培维索孟治疗体内或体外时，对前列腺癌细胞中 pegvisomant 的调节相似，表明 GH 通过 GHR 激活直接调节前列腺癌细胞，而其他基因仅在体内对 pegvisomant 有反应，表明 pegvisomant 对宿主内分泌环境的间接调节。从鼠转基因腺癌前列腺（TRAMP）模型衍生的前列腺癌细胞系中也观察到了类似的结果。
