mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency.
mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency.
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mTORC1 介导的 COX2 下调抑制 TSC2 缺陷引起的肿瘤生长
DOI：
10.18632/oncotarget.8633
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Zha X
中科院分区：
文献类型：
--
作者：
Li H;Jin F;Jiang K;Ji S;Wang L;Ni Z;Chen X;Hu Z;Zhang H;Liu Y;Qin Y;Zha X
由TSC 1或TSC 2基因的功能丧失突变引起的多发性硬化症（TSC）的特征是多个器官中的良性肿瘤形成。哺乳动物雷帕霉素复合物靶蛋白1（mTORC 1）的过度活化是TSC肿瘤的主要改变。通过分析Tsc 2-null小鼠胚胎成纤维细胞（MEFs）和大鼠子宫平滑肌瘤衍生的Tsc 2-null ELT 3细胞，我们检测到环氧化酶2（COX 2）作为mTORC 1的下游靶点参与TSC肿瘤发展的证据。我们发现TSC 2的缺失通过激活mTORC 1/信号转导子和转录激活子3（STAT 3）信号通路导致COX 2表达降低。COX 2的过表达促进Tsc 2-null细胞的增殖和肿瘤生长。COX 2敲低抑制对照细胞的增殖。COX 2通过上调白细胞介素-6（IL-6）促进Tsc 2-null细胞生长。此外，雷帕霉素与塞来昔布（一种COX 2抑制剂）组合强烈抑制Tsc 2缺陷细胞的生长。我们的结论是COX 2的下调对过度活化的mTORC 1介导的肿瘤发生产生保护作用，由TSC 2的损失引起，雷帕霉素和塞来昔布的组合可能是一种有效的新方法来治疗TSC。
Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 gene, is characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) is the primary alteration underlying TSC tumors. By analyzing Tsc2-null mouse embryonic fibroblasts (MEFs) and rat uterine leiomyoma-derived Tsc2-null ELT3 cells, we detected evidence for the involvement of cyclooxygenase 2 (COX2) as a downstream target of mTORC1 in the development of TSC tumors. We showed that loss of TSC2 led to decreased COX2 expression through activation of an mTORC1/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Overexpression of COX2 promoted proliferation and tumoral growth of Tsc2-null cells. COX2 knockdown inhibited the proliferation of the control cells. COX2 enhanced Tsc2-null cell growth through upregulation of interleukin-6 (IL-6). In addition, rapamycin in combination with celecoxib, a COX2 inhibitor, strongly inhibited Tsc2-deficient cell growth. We conclude that downregulation of COX2 exerts a protective effect against hyperactivated mTORC1-mediated tumorigenesis caused by the loss of TSC2, and the combination of rapamycin and celecoxib may be an effective new approach to treating TSC.
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影响因子：
5.2
作者：
Orlova KA;Crino PB
通讯作者：
Crino PB
影响因子：
--
作者：
Liang S;Salas T;Gencaslan E;Li B;Habib SL
通讯作者：
Habib SL
影响因子：
--
作者：
Kannan A;Lin Z;Shao Q;Zhao S;Fang B;Moreno MA;Vural E;Stack BC Jr;Suen JY;Kannan K;Gao L
通讯作者：
Gao L
DOI：
10.1158/1078-0432.ccr-09-0788
发表时间：
2010-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Menter DG;Schilsky RL;DuBois RN
通讯作者：
DuBois RN
脑表达的 X 连锁 2 对于雷帕霉素 (mTOR) 介导的肿瘤发生的高活性机制靶点至关重要
影响因子：
4.8
作者：
Hu, Zhongdong;Wang, Ying;Zhang, Hongbing
通讯作者：
Zhang, Hongbing