Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer.
Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer.
复制标题
DOI：
10.1158/1535-7163.mct-09-0980
复制
发表时间：
2010-10
影响因子：
5.7
通讯作者：
Meric-Bernstam F
中科院分区：
文献类型：
--
作者：
Luyimbazi D;Akcakanat A;McAuliffe PF;Zhang L;Singh G;Gonzalez-Angulo AM;Chen H;Do KA;Zheng Y;Hung MC;Mills GB;Meric-Bernstam F
雷帕霉素的哺乳动物靶点（mTOR）信号通路是蛋白质翻译、细胞生长和代谢的核心调节因子。mTOR信号通路的改变在癌症中很常见，这使得mTOR成为一个有前景的治疗靶点。在临床试验中，雷帕霉素类似物对大多数癌症类型（包括乳腺癌）显示出适度的反应率。因此，迫切需要更好地理解雷帕霉素的作用机制，以便改善患者选择并监测通路抑制情况。为了确定雷帕霉素活性的新型药效学标志物，我们对代表不同亚型的三种乳腺癌细胞系中的总RNA和多聚核糖体相关RNA进行了转录谱分析。在所有三种细胞系中，我们发现雷帕霉素显著降低了硬脂酰 - 辅酶A去饱和酶1（SCD1）的多聚核糖体相关mRNA水平，SCD1是单不饱和脂肪酸合成中的限速酶。mTOR激活剂增加了SCD1蛋白表达，而雷帕霉素、LY294002和BEZ235降低了SCD1蛋白表达。雷帕霉素降低了总SCD1 RNA表达，但没有导致其相对多聚核糖体募集（多聚核糖体/总比值）显著下降。雷帕霉素没有改变SCD1 mRNA的稳定性。相反，雷帕霉素抑制了SCD1启动子活性并降低了成熟转录因子固醇调节元件结合蛋白1（SREBP1）的表达。真核起始因子4E（eIF4E）的小干扰RNA（siRNA）降低了SCD1和SREBP1的表达，表明SCD1可能通过mTOR/ eIF4E结合蛋白1轴受到调节。此外，SCD1的小干扰RNA敲低抑制了乳腺癌细胞生长，而其过表达则促进生长。综上所述，这些发现表明雷帕霉素降低了SCD1表达，在细胞信号传导与癌细胞脂肪酸合成和生长之间建立了重要联系。
mTOR (mammalian target of rapamycin) signaling is a central regulator of protein translation, cell growth and metabolism. Alterations of the mTOR signaling pathway are common in cancer, making mTOR a promising therapeutic target. In clinical trials, rapamycin analogs have shown modest response rates for most cancer types, including breast cancer. Therefore, there is an urgent need to better understand rapamycin’s mechanism of action, in order to improve patient selection and to monitor pathway inhibition. To identify novel pharmacodynamic markers of rapamycin activity, we performed transcriptional profiling of total and polysome-associated RNA in three breast cancer cell lines representing different subtypes. In all three cell lines, we found that rapamycin significantly decreased polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Activators of mTOR increased SCD1 protein expression, while rapamycin, LY294002 and BEZ235 decreased SCD1 protein expression. Rapamycin decreased total SCD1 RNA expression without inducing a significant decline in its relative polysomal recruitment (polysome/total ratio). Rapamycin did not alter SCD1 mRNA stability. Instead, rapamycin inhibited SCD1 promoter activity and decreased expression of mature transcription factor sterol regulatory element binding protein 1 (SREBP1). Eukaryotic initiation factor 4E (eIF4E) siRNA decreased both SCD1 and SREBP1 expression, suggesting SCD1 may be regulated through the mTOR/eIF4E-binding protein 1 axis. Furthermore, SCD1 siRNA knockdown inhibited breast cancer cell growth, while over-expression increased growth. Taken together these findings demonstrate that rapamycin decreases SCD1 expression, establishing an important link between cell signaling and cancer cell fatty acid synthesis and growth.