Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas.
Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas.
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DOI：
10.1158/0008-5472.can-10-1873
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Moran RG
中科院分区：
文献类型：
--
作者：
Rothbart SB;Racanelli AC;Moran RG
化疗药物培美曲塞是胸苷酸合成酶的抑制剂，在人类白血病细胞AICART中有一个重要的次要靶点，AICART是嘌呤生物合成的第二叶酸依赖酶。聚集在该区块后面的嘌呤中间体氨基咪唑甲酰胺核苷酸(ZMP)通过激活细胞能量传感器AMPK向mTORC1复合体传递抑制信号。鉴于PI3K-AKT-mTOR通路在癌变过程中经常被解除调控，我们询问培美曲塞间接激活AMPK是否为该通路缺陷的癌症提供了一种有效的治疗策略。在培美曲塞治疗的结肠癌和肺癌细胞中，ZMP对AMPK的激活以及这种激活的下游后果明显比以前在白血病细胞中看到的更强劲。基因实验证实了AICART抑制和AMPK激活在这些效应中的中介作用。虽然AMPK的激活导致mTORC1的显著抑制，但AMPK的其他靶点被磷酸化，而不是mTORC1依赖的。虽然AMPK的激活被认为需要AMPKαT172的磷酸化，但培美曲塞也激活了癌细胞中的AMPK，而LKB1是主要的AMPKαT172激酶，其缺失在肺腺癌中很常见。与雷帕霉素类似物一样，培美曲塞解除了对PI3K和AKT的反馈抑制，但在AMPK激活后，发现未磷酸化的4E-BP1长期积累，这是一种紧密结合的帽依赖翻译抑制物。我们的发现表明，培美曲塞激活AMPK抑制了控制翻译和脂代谢的mTORC1依赖和非依赖性过程，从而确定培美曲塞是这一途径的靶向治疗剂，这一途径与雷帕霉素类似物有显著不同。
The chemotherapeutic drug pemetrexed, an inhibitor of thymidylate synthase, has an important secondary target in human leukemic cells, AICART, the second folate-dependent enzyme of purine biosynthesis. The purine intermediate aminoimidazolecarboxamide ribonucleotide (ZMP), which accumulates behind this block, transmits an inhibitory signal to the mTORC1 complex via activation of the cellular energy sensor AMPK. Given that the PI3K-AKT-mTOR pathway is frequently deregulated during carcinogenesis, we asked whether the indirect activation of AMPK by pemetrexed offers an effective therapeutic strategy for carcinomas with defects in this pathway. Activation of AMPK by ZMP in pemetrexed-treated colon and lung carcinoma cells and the downstream consequences of this activation were strikingly more robust than previously seen in leukemic cells. Genetic experiments demonstrated the intermediacy of AICART inhibition and the centrality of AMPK activation in these effects. While AMPK activation resulted in marked inhibition of mTORC1, other targets of AMPK were phosphorylated that were not mTORC1-dependent. Whereas AMPK activation is thought to require AMPKα T172 phosphorylation, pemetrexed also activated AMPK in carcinoma cells null for LKB1, the predominant AMPKα T172 kinase whose deficiency is common in lung adenocarcinomas. Like rapamycin analogs, pemetrexed relieved feedback suppression of PI3K and AKT, but the prolonged accumulation of unphosphorylated 4E-BP1, a tight-binding inhibitor of cap-dependent translation, was seen following AMPK activation. Our findings indicate that AMPK activation by pemetrexed inhibits mTORC1- dependent and -independent processes that control translation and lipid metabolism, identifying pemetrexed as a targeted therapeutic agent for this pathway that differs significantly from rapamycin analogs.