von Roemeling Christina A, Marlow Laura A, Pinkerton Anthony B, Crist Angela, Miller James, Tun Han W, Smallridge Robert C, Copland John A
Departments of Cancer Biology (C.A.v.R., L.A.M., A.C., J.M., H.W.T., R.C.S., J.A.C.) and Hematology and Oncology (H.W.T.), and Division of Endocrinology and Metabolism (R.C.S.), Mayo Clinic, Jacksonville, Florida, 32224; The Mayo Clinic Graduate School (C.A.v.R.), Rochester, Minnesota 55905; and Conrad Prebys Center for Chemical Genomics (A.B.P.), Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
J Clin Endocrinol Metab. 2015 May;100(5):E697-709. doi: 10.1210/jc.2014-2764. Epub 2015 Feb 12.
Currently there are no efficacious therapies for patients with anaplastic thyroid carcinoma (ATC) that result in long-term disease stabilization or regression.
We sought to identify pathways critical for ATC cell progression and viability in an effort to develop new therapeutic strategies. We investigated the effects of targeted inhibition of stearoyl-CoA desaturase 1 (SCD1), a constituent of fatty acid metabolism overexpressed in ATC.
A gene array of ATC and normal thyroid tissue was performed to identify gene transcripts demonstrating altered expression in tumor samples. Effects of pharmacological and the genetic inhibition of SCD1 on tumor cell viability as well as cell signaling responses to therapy were evaluated in in vitro and in vivo models of this rare, lethal malignancy.
The gene array analysis revealed consistent distortion of fatty acid metabolism and overexpression of SCD1 in ATC and well-differentiated thyroid carcinomas. SCD1 is critical for ATC cell survival and proliferation, the inhibition of which induced endoplasmic reticulum stress, activation of the unfolded protein response, and apoptosis. Combined suppression of endoplasmic reticulum-associated degradation, a prosurvival component of the unfolded protein response, using proteasome inhibitors resulted in a synergistic decrease in tumor cell proliferation and increased cell death.
SCD1 is a novel oncogenic factor specifically required for tumor cell viability in ATC. Furthermore, the expression of SCD1 appears to be correlated with thyroid tumor aggressiveness and may serve as a prognostic biomarker. These findings substantiate SCD1 as a novel tumor-specific target for therapy in patients with ATC and should be further investigated in a clinical setting.
目前对于间变性甲状腺癌（ATC）患者尚无有效的治疗方法能实现长期疾病稳定或缓解。
我们试图确定对ATC细胞进展和生存至关重要的途径，以开发新的治疗策略。我们研究了靶向抑制硬脂酰辅酶A去饱和酶1（SCD1）的作用，SCD1是一种在ATC中过表达的脂肪酸代谢成分。
对ATC和正常甲状腺组织进行基因阵列分析，以鉴定在肿瘤样本中表达改变的基因转录本。在这种罕见的致命恶性肿瘤的体外和体内模型中，评估了SCD1的药理抑制和基因抑制对肿瘤细胞活力以及细胞对治疗的信号反应的影响。
基因阵列分析显示ATC和高分化甲状腺癌中脂肪酸代谢持续紊乱且SCD1过表达。SCD1对ATC细胞存活和增殖至关重要，抑制它会诱导内质网应激、激活未折叠蛋白反应并导致细胞凋亡。使用蛋白酶体抑制剂联合抑制内质网相关降解（未折叠蛋白反应的一种促生存成分）可协同降低肿瘤细胞增殖并增加细胞死亡。
SCD1是ATC中肿瘤细胞存活特别需要的一种新型致癌因子。此外，SCD1的表达似乎与甲状腺肿瘤侵袭性相关，可能作为一种预后生物标志物。这些发现证实SCD1是ATC患者治疗的新型肿瘤特异性靶点，应在临床环境中进一步研究。
