Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA.
Clin Cancer Res. 2013 May 1;19(9):2368-80. doi: 10.1158/1078-0432.CCR-12-3249. Epub 2013 Apr 30.
We set out to identify Stearoyl-CoA desaturase 1 (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 U.S. Food and Drug Administration (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 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.
我们旨在确定硬脂酰辅酶 A 去饱和酶 1（SCD1）是透明细胞肾细胞癌（ccRCC）中的一个新的分子靶点，并研究其在体外和体内独立以及与当前美国食品和药物管理局（FDA）批准的方案联合使用时对肿瘤细胞生长和活力的作用。
检查患者正常和 ccRCC 组织样本和细胞系中 SCD1 的表达情况。通过使用小分子抑制剂 A939572 进行基因敲低模型和 SCD1 的靶向抑制，分析生长、凋亡和基因表达的变化，使用基因芯片分析。通过用酪氨酸激酶抑制剂（TKI）舒尼替尼和帕唑帕尼以及 mTOR 抑制剂替西罗莫司抑制 SCD1 的药理学抑制来评估协同治疗模型。
我们的研究确定 SCD1 在 ccRCC 的所有阶段表达增加。基因敲低和 SCD1 的药理学抑制均减少了体外和体内肿瘤细胞的增殖并诱导了凋亡。在用 A939572 处理或 SCD1 慢病毒敲低样本进行基因芯片、定量实时 PCR 和蛋白质分析后，观察到内质网应激反应信号的诱导，为 SCD1 在 ccRCC 中的活性提供了机制见解。此外，A939572 与替西罗莫司联合应用在体外和体内均协同抑制肿瘤生长。
SCD1 表达增加支持 ccRCC 的存活，因此我们建议将其作为一种新的分子靶点，用于治疗该疾病，无论是独立应用还是与 mTOR 抑制剂联合应用，用于那些不能通过手术干预来治疗的患者，例如在晚期或转移性疾病的情况下。
