胰岛素样生长因子和 mTOR 通路表达及替西罗莫司和 mTOR 抑制剂在肾上腺皮质癌中的体外作用。

IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer.

机构信息

Department of Internal Medicine, Division Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.

Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy.

出版信息

Endocrine. 2019 Jun;64(3):673-684. doi: 10.1007/s12020-019-01869-1. Epub 2019 Mar 5.

PURPOSE

The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC.

METHODS

The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated.

RESULTS

A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect.

CONCLUSIONS

In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.

目的

胰岛素样生长因子（IGF）和哺乳动物雷帕霉素靶蛋白（mTOR）途径被认为是治疗肾上腺皮质癌（ACC）患者的潜在靶点。本研究旨在描述 ACC 中的 IGF 途径，并探讨 IGF1R/IR 抑制剂 lin-丝裂原激活蛋白激酶（MAPK）激酶（MAPK）抑制剂和 mTOR 抑制剂（西罗莫司和依维莫司）联合治疗在 ACC 体外模型中的反应。

方法

通过免疫组织化学法检测 17 例人 ACC 中 IGF2、IGF1R 和 IGF2R 的蛋白表达水平，并通过 RT-qPCR 检测 12 例样本中 IGF1、IGF2、IGF1R、IR 同工型 A 和 B、IGF2R、IGF 结合蛋白[IGFBP]-1、2、3 和 6 的 mRNA 表达水平。在 H295R 和 HAC15 ACC 细胞系中，评估了 lin-丝裂原激活蛋白激酶（MAPK）激酶（MAPK）抑制剂和西罗莫司或依维莫司联合应用对细胞存活的影响。

结果

IGF2、IGF1R 和 IGF2R 的蛋白表达水平分别在 82%、65%和 100%的样本中较高。大多数样本中 IGF2 mRNA 的相对表达水平较高。在大多数样本中，IRA 的 mRNA 水平高于 IRB 和 IGF1R（75%）。Lin-丝裂原激活蛋白激酶（MAPK）激酶（MAPK）抑制剂抑制 H295R 和 HAC15 细胞系的细胞生长，并且与西罗莫司或依维莫司联合应用时，lin-丝裂原激活蛋白激酶（MAPK）激酶（MAPK）抑制剂显示出显著的相加作用。

结论

除 IGF2 和 IGF1R 外，ACC 还表达 IGF2R、IRA 和几种 IGFBPs，这表明 ACC 中 IGF 途径的不同成分之间的相互作用可能比以前认为的更为复杂。与单独使用 lin-丝裂原激活蛋白激酶（MAPK）激酶（MAPK）抑制剂相比，mTOR 抑制剂的加入可能具有更强的抗增殖作用。