Targeting a ribonucleoprotein complex containing the caprin-1 protein and the c-Myc mRNA suppresses tumor growth in mice: an identification of a novel oncotarget.
Targeting a ribonucleoprotein complex containing the caprin-1 protein and the c-Myc mRNA suppresses tumor growth in mice: an identification of a novel oncotarget.
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DOI：
10.18632/oncotarget.3236
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
Lee SJ
中科院分区：
文献类型：
--
作者：
Qiu YQ;Yang CW;Lee YZ;Yang RB;Lee CH;Hsu HY;Chang CC;Lee SJ
几十年来，Tylophorine化合物一直是药物开发的焦点。tylophine衍生物具有抗癌活性，但其细胞靶点尚不清楚。我们使用生物素化霉霉啉衍生物来探测霉霉啉相互作用的细胞靶标。Tylophorine直接与capin -1结合，从而增强G3BP1、c-Myc mRNA和cyclin D2 mRNA的募集，形成核糖核蛋白复合物。随后，这种斑疹碱靶向核糖核蛋白复合物被隔离到多体部分，相关mrna转录物的蛋白质表达被抑制。Caprin-1缺失的癌细胞对tylophine更有抵抗力，这与tylophine靶向的核糖核蛋白复合物的形成减少有关。因此，tylophine下调c-Myc和细胞周期蛋白D1/D2，导致Rb的低磷酸化，抑制加工体的形成和Warburg效应。基因表达谱和c-Myc功能获得实验也显示，下调的c-Myc参与了tylophorine化合物的抗癌作用。此外，强效的tylophorine衍生物dibenzoquinoline-33b也引起了类似的效果，因为用dibenzoquinoline-33b治疗的异种移植肿瘤中c-Myc蛋白水平也降低了。因此，tylophorine化合物主要通过靶向和隔离capin -1蛋白和c-Myc mRNA相关核糖核蛋白复合物来发挥抗癌活性。
Tylophorine compounds have been the focus of drug development for decades. Tylophorine derivatives exhibit anti-cancer activities but their cellular targets remain unknown. We used a biotinylated tylophorine derivative to probe for the interacting cellular target(s) of tylophorine. Tylophorine directly binds to caprin-1 and consequently enhances the recruitment of G3BP1, c-Myc mRNA, and cyclin D2 mRNA to form a ribonucleoprotein complex. Subsequently, this tylophorine targeted ribonucleoprotein complex is sequestered to the polysomal fractions and the protein expressions of the associated mRNA-transcripts are repressed. Caprin-1 depleted carcinoma cells become more resistant to tylophorine, associated with decreased formation of the ribonucleoprotein complex targeted by tylophorine. Consequently, tylophorine downregulates c-Myc and cyclins D1/D2, causing hypophosphorylation of Rb and suppression of both processing-body formation and the Warburg effect. Gene expression profiling and gain-of-c-Myc-function experiments also revealed that the downregulated c-Myc contributes to the anti-oncogenic effects of tylophorine compounds. Furthermore, the potent tylophorine derivative dibenzoquinoline-33b elicited a similar effect, as c-Myc protein levels were also decreased in xenograft tumors treated with dibenzoquinoline-33b. Thus, tylophorine compounds exert anti-cancer activity predominantly by targeting and sequestering the caprin-1 protein and c-Myc mRNA associated ribonucleoprotein complex.
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影响因子：
8
作者：
Bowe, DB;Kenney, NJ;Maroulakou, IG
通讯作者：
Maroulakou, IG
影响因子：
5.4
作者：
Amorim, Maria Joao;Kao, Richard Y.;Digard, Paul
通讯作者：
Digard, Paul
影响因子：
7.3
作者：
Lee, Yue-Zhi;Yang, Cheng-Wei;Lee, Shiow-Ju
通讯作者：
Lee, Shiow-Ju
影响因子：
4.3
作者：
Labisso, Wajana L.;Wirth, Matthias;Schneider, Guenter
通讯作者：
Schneider, Guenter
影响因子：
64.5
作者：
Lin CY;Lovén J;Rahl PB;Paranal RM;Burge CB;Bradner JE;Lee TI;Young RA
通讯作者：
Young RA