Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.
Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.
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DOI：
10.1084/jem.20110846
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发表时间：
2011-08-29
期刊：
影响因子：
--
通讯作者：
Wendel HG
中科院分区：
文献类型：
--
作者：
Schatz JH;Oricchio E;Wolfe AL;Jiang M;Linkov I;Maragulia J;Shi W;Zhang Z;Rajasekhar VK;Pagano NC;Porco JA Jr;Teruya-Feldstein J;Rosen N;Zelenetz AD;Pelletier J;Wendel HG
人类淋巴瘤中PIM激酶的表达可以影响化疗的结果，并且阻断帽依赖性翻译可以逆转小鼠淋巴瘤中PIM介导的雷帕霉素抗性。靶向致癌信号分子的新抗癌药物极大地改善了某些癌症的治疗。然而，对靶向治疗的抗性是一个主要的临床问题，并且致癌信号通路的冗余提供了允许癌细胞逃逸的备用机制。例如，AKT和PIM激酶产生平行的致癌信号，并共享许多分子靶标，包括帽依赖性翻译的激活剂。在这里，我们表明PIM激酶的表达可以影响淋巴瘤化疗的临床结果。我们在动物淋巴瘤模型中观察到相同的情况。而由AKT引起的耐药性很容易用雷帕霉素逆转，PIM介导的耐药性对mTORC 1抑制是难治的。然而，PIM和AKT表达淋巴瘤都依赖于帽依赖性翻译，并且翻译起始复合物的遗传或药理学阻断对这些肿瘤非常有效。阻断帽依赖性翻译的治疗效果至少部分是通过减少短寿命癌蛋白（包括c-MYC、细胞周期蛋白D1、MCL 1和PIM 1/2激酶本身）的产生来介导的。因此，靶向致癌存活信号在翻译起始上的会聚是激酶抑制剂组合的有效替代方案。
PIM kinase expression in human lymphomas can influence the outcome of chemotherapy, and blocking cap-dependent translation can reverse PIM-mediated rapamycin resistance in murine lymphomas. New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors.
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