Division of Endocrinology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Endocr Relat Cancer. 2012 May 24;19(3):351-64. doi: 10.1530/ERC-11-0270. Print 2012 Jun.
Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production. Moreover, the effects of sirolimus on basal and IGF2-stimulated H295 cell colony growth and on basal and IGF1-stimulated phospho-AKT, phospho-S6K1, and phospho-ERK in H295 and SW13 were studied. Finally, we have evaluated the effects of combination treatment of sirolimus with an IGF2-neutralizing antibody. We have found that H295 and HAC15 expressed IGF2 at a >1800-fold higher level than SW13. mTOR inhibitors suppressed cell growth in a dose-/time-dependent manner in all cell lines. SW13 were the most sensitive to these effects. Sirolimus inhibited H295 colony surviving fraction and size. These effects were not antagonized by IGF2, suggesting the involvement of other autocrine regulators of mTOR pathways. In H295, sirolimus activated escape pathways. The blocking of endogenously produced IGF2 increased the antiproliferative effects of sirolimus on H295. Cortisol production by H295 and HAC15 was inhibited by sirolimus. The current study demonstrates that mTOR inhibitors inhibit the proliferation and cortisol production in ACC cells. Different ACC cells have different sensitivity to the mTOR inhibitors. mTOR could be a target for the treatment of human ACCs, but variable responses might be expected. In selected cases of ACC, the combined targeting of mTOR and IGF2 could have greater effects than mTOR inhibitors alone.
患有肾上腺皮质癌 (ACC) 的患者需要新的治疗选择。本研究旨在评估 mTOR 抑制剂西罗莫司和替西罗莫司对人 ACC 细胞生长和皮质醇产生的影响。在 H295、HAC15 和 SW13 细胞中，我们评估了 mTOR、IGF2 和 IGF1 受体的表达；西罗莫司和替西罗莫司对细胞生长的影响；西罗莫司对细胞凋亡、细胞周期和皮质醇产生的影响。此外，我们还研究了西罗莫司对 H295 细胞基础和 IGF2 刺激集落生长以及 H295 和 SW13 中基础和 IGF1 刺激磷酸化 AKT、磷酸化 S6K1 和磷酸化 ERK 的影响。最后，我们评估了西罗莫司与 IGF2 中和抗体联合治疗的效果。我们发现 H295 和 HAC15 表达的 IGF2 比 SW13 高 1800 多倍。mTOR 抑制剂以剂量和时间依赖的方式抑制所有细胞系的细胞生长。SW13 对这些作用最敏感。西罗莫司抑制 H295 集落存活分数和大小。这些作用不受 IGF2 的拮抗，表明 mTOR 途径的其他自分泌调节剂参与其中。在 H295 中，西罗莫司激活逃逸途径。内源性产生的 IGF2 的阻断增加了西罗莫司对 H295 的抗增殖作用。H295 和 HAC15 的皮质醇产生被西罗莫司抑制。本研究表明，mTOR 抑制剂抑制 ACC 细胞的增殖和皮质醇产生。不同的 ACC 细胞对 mTOR 抑制剂的敏感性不同。mTOR 可能是治疗人类 ACC 的靶点，但可能会出现不同的反应。在某些 ACC 病例中，mTOR 和 IGF2 的联合靶向可能比单独使用 mTOR 抑制剂具有更大的效果。
