文章：

p21Waf1/Cip1是40S核糖体S6激酶2的新型下游靶点

p21Waf1/Cip1Is a Novel Downstream Target of 40S Ribosomal S6 Kinase 2

原文发布日期：10 November 2024

DOI: 10.3390/cancers16223783

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: The ribosomal S6 kinase 2 (S6K2) acts downstream of the mechanistic target of rapamycin complex 1 and is a homolog of S6K1 but little is known about its downstream effectors. The objective of this study was to use an unbiased transcriptome profiling to uncover how S6K2 promotes breast cancer cell survival.Methods: RNA-Seq analysis was performed to identify novel S6K2 targets. Cells were transfected with siRNAs or plasmids containing genes of interest. Western blot analyses were performed to quantify total and phosphorylated proteins. Apoptosis was monitored by treating cells with different concentrations of doxorubicin.Results: Silencing of S6K2, but not S6K1, decreased p21 in MCF-7 and T47D breast cancer cells. Knockdown of Akt1 but not Akt2 decreased p21 in MCF-7 cells whereas both Akt1 and Akt2 knockdown attenuated p21 in T47D cells. While Akt1 overexpression enhanced p21 and partially reversed the effect of S6K2 deficiency on p21 downregulation in MCF-7 cells, it had little effect in T47D cells. S6K2 knockdown increasedJUNmRNA and knockdown of cJun enhanced p21. Low concentrations of doxorubicin increased, and high concentrations decreased p21 levels in T47D cells. Silencing of S6K2 or p21 sensitized T47D cells to doxorubicin via c-Jun N-terminal kinase (JNK)-mediated downregulation of Mcl-1.Conclusions: S6K2 knockdown enhanced doxorubicin-induced apoptosis by downregulating the cell cycle inhibitor p21 and the anti-apoptotic protein Mcl-1 via Akt and/or JNK.

摘要翻译： 

背景/目的：核糖体S6激酶2（S6K2）位于雷帕霉素机制靶点复合物1的下游，是S6K1的同源蛋白，但其下游效应分子尚不明确。本研究旨在通过无偏转录组分析揭示S6K2促进乳腺癌细胞存活的机制。方法：采用RNA测序技术鉴定新型S6K2靶点。通过siRNA或含目的基因的质粒转染细胞。采用蛋白质印迹法检测总蛋白及磷酸化蛋白水平。通过不同浓度阿霉素处理细胞监测细胞凋亡情况。结果：在MCF-7和T47D乳腺癌细胞中，沉默S6K2（而非S6K1）可降低p21表达。MCF-7细胞中Akt1（而非Akt2）敲低可降低p21，而T47D细胞中Akt1与Akt2敲低均能减弱p21表达。在MCF-7细胞中过表达Akt1可提升p21水平并部分逆转S6K2缺失导致的p21下调，但在T47D细胞中作用不明显。S6K2敲低可增加JUN mRNA表达，而敲低cJun则增强p21表达。低浓度阿霉素可提升T47D细胞p21水平，高浓度则降低其表达。沉默S6K2或p21通过c-Jun氨基末端激酶（JNK）介导的Mcl-1下调增强T47D细胞对阿霉素的敏感性。结论：S6K2敲低通过Akt和/或JNK通路下调细胞周期抑制蛋白p21与抗凋亡蛋白Mcl-1，从而增强阿霉素诱导的细胞凋亡。

原文链接：

p21Waf1/Cip1Is a Novel Downstream Target of 40S Ribosomal S6 Kinase 2