CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway.
CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway.
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CGP57380 通过消除 mTOR 抑制诱导的 eIF4E 磷酸化并激活线粒体凋亡途径，增强 RAD001 在非小细胞肺癌中的疗效
DOI：
10.18632/oncotarget.8497
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Fan S
中科院分区：
文献类型：
--
作者：
Wen Q;Wang W;Luo J;Chu S;Chen L;Xu L;Zang H;Alnemah MM;Ma J;Fan S
哺乳动物雷帕霉素靶蛋白（mTOR）是一个潜在的重要的治疗靶点，在广泛的癌症类型。mTOR抑制剂如雷帕霉素及其类似物（rapalogs）已被证明在非小细胞肺癌（NSCLC）中作为抗癌剂是有效的，而它们强烈增强真核翻译起始因子4E（eIF4E）的磷酸化和Akt的活化，这在初始应答后引起对mTOR靶向治疗的抗性。雷帕霉素通过激活MAPK相互作用激酶（Mnks）诱导eIF4E磷酸化，因此靶向Mnk/eIF4E通路代表了治疗NSCLC的潜在治疗策略。我们的研究结果表明，p-Mnk 1和p-eIF4 E的过表达与NSCLC患者的总生存率显著相关，p-Mnk 1的高表达可能作为这些患者的独立预后生物标志物。同时，通过Mnk抑制剂（CGP57380）抑制Mnk1表达可以消除雷帕霉素类似物（RAD001）诱导的eIF4E磷酸化和Akt活化。CGP57380与RAD001联合应用可通过激活线粒体内源性途径诱导NSCLC细胞凋亡，在体内外均发挥协同抗肿瘤作用。总之，靶向mTOR和Mnk/eIF4E信号通路的组合以增强mTOR靶向癌症治疗的有效性可能是NSCLC个性化治疗的重大创新。
The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and activation of Akt, which cause resistance to mTOR-targeted therapy after an initial response. Rapamycin induces eIF4E phosphorylation by activating MAPK-interacting kinases (Mnks), and therefore targeting Mnk/eIF4E pathway represents a potential therapeutic strategy for the treatment of NSCLC. Here, our results showed that over-expression of p-Mnk1 and p-eIF4E was significantly associated with poor overall survival of NSCLC patients and high expression of p-Mnk1 might act as an independent prognostic biomarker for these patients. Meanwhile, inhibiting Mnk1 expression by Mnk inhibitor (CGP57380) could abrogate rapalogs (RAD001)-induced eIF4E phosphorylation and Akt activation. Furthermore, combination of CGP57380 and RAD001 could induce NSCLC cells apoptosis via activating intrinsic mitochondrial pathway, and exert synergistic antitumor efficacy both in vitro and in vivo. In conclusion, combination of targeting both mTOR and Mnk/eIF4E signaling pathways to enhance effectiveness of mTOR-targeted cancer therapy might be significant innovation for the personalized treatment of NSCLC.
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DOI：
10.1073/pnas.1005320107
发表时间：
2010-08-10
影响因子：
11.1
作者：
Furic, Luc;Rong, Liwei;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum
影响因子：
4.8
作者：
Li, Yikun;Yue, Ping;Sun, Shi-Yong
通讯作者：
Sun, Shi-Yong
对BCL-2生物学的新兴理解：对肿瘤进展和治疗的影响。
DOI：
10.1016/j.bbamcr.2015.03.012
发表时间：
2015-07
影响因子：
5.1
作者：
Correia, Cristina;Lee, Sun-Hee;Meng, X. Wei;Vincelette, Nicole D.;Knorr, Katherine L. B.;Ding, Husheng;Nowakowski, Grzegorz S.;Dai, Haiming;Kaufmann, Scott H.
通讯作者：
Kaufmann, Scott H.
DOI：
10.1158/1078-0432.ccr-10-0433
发表时间：
2010-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hsieh AC;Ruggero D
通讯作者：
Ruggero D
DOI：
10.1073/pnas.1301838110
发表时间：
2013-06-18
影响因子：
11.1
作者：
Lim, Sharon;Saw, Tzuen Yih;Ong, S. Tiong
通讯作者：
Ong, S. Tiong