Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma.
Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma.
复制标题
DOI：
10.1158/1078-0432.ccr-12-3249
复制
发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Copland JA
中科院分区：
文献类型：
--
作者：
von Roemeling CA;Marlow LA;Wei JJ;Cooper SJ;Caulfield TR;Wu K;Tan WW;Tun HW;Copland JA
我们着手将SCD 1鉴定为透明细胞肾细胞癌（ccRCC）中的新型分子靶点，并独立地以及与当前FDA批准的方案组合地检查其在体外和体内肿瘤细胞生长和活力中的作用。检查患者正常和ccRCC组织样品和细胞系的SCD 1表达。基因敲除模型和通过使用小分子抑制剂A939572对SCD 1进行靶向抑制，使用基因阵列分析来分析生长、凋亡和基因表达的改变。利用酪氨酸激酶抑制剂（TKI）舒尼替尼和帕唑帕尼以及mTOR抑制剂替西罗莫司对SCD 1的药理学抑制来评估协同作用的治疗模型。我们的研究确定了在所有阶段的ccRCC中增加的SCD 1表达。在体外和体内，SCD 1的基因敲除和药理学抑制均降低肿瘤细胞增殖并诱导凋亡。在A939572处理的或SCD 1慢病毒敲低样品的基因阵列、定量实时PCR和蛋白质分析后，观察到内质网（ER）应激反应信号传导的诱导，为ccRCC中SCD 1活性提供了机制见解。此外，A939572与替西罗莫司的组合应用在体外和体内协同抑制肿瘤生长。增加的SCD 1表达支持ccRCC活力，因此我们提出将其作为一种新的分子靶点，用于单独治疗或与mTOR抑制剂联合治疗无法通过手术干预治疗的患者，例如晚期或转移性疾病。
We set out to identify SCD1 as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current FDA approved regimens. Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572 treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum (ER) stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease.