Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via Hyper-induction of p53 (Retracted article. See vol. 293, pg. 18015, 2018)
Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via Hyper-induction of p53 (Retracted article. See vol. 293, pg. 18015, 2018)
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DOI：
10.1074/jbc.m704432200
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发表时间：
2008-02-15
影响因子：
4.8
通讯作者：
Ha, Joohun
中科院分区：
文献类型：
--
作者：
Kim, Hak-Su;Hwang, Jin-Taek;Ha, Joohun
顺铂是最有效和最广泛使用的化疗药物之一。然而，顺铂的临床应用的最突出的限制之一是一些肿瘤表现出的获得性或内在耐药性。在本研究中，我们评估了细胞内能量平衡系统作为增强肿瘤顺铂敏感性的靶点的潜力。AMP活化蛋白激酶（AMPK）通过监测细胞内能量状态来调节能量平衡系统。在这里，我们证明了AMPK在AGS和HCT 116癌细胞中被顺铂快速激活。AMPK在这些细胞和HCT 116异种移植物中的抑制导致顺铂诱导的细胞凋亡显著增加，这与肿瘤抑制因子p53的过度诱导有关。我们进一步表明，ERK，而不是ATM（共济失调毛细血管扩张突变）和ATR（ATM和Rad3相关）激酶，参与了通过抑制顺铂诱导的AMPK过度诱导p53。相比之下，顺铂不会诱导HeLa细胞中的AMPK活化，HeLa细胞似乎对顺铂诱导的细胞毒性具有相对较高的敏感性，但HeLa细胞中AMPK组成型活性形式的表达导致细胞活力显着增加。顺铂处理。总的来说，我们的数据表明，AMPK执行一个关键的功能，保护对顺铂的细胞毒性作用，从而意味着AMPK是决定细胞对顺铂的敏感性的细胞因子之一。基于这些观察结果，我们提出了一种结合顺铂和AMPK抑制的策略，可以发展成为一种新的化疗方式。
Cisplatin is one of the most effective and widely used chemotherapeutic agents. However, one of the most salient limitations to the clinical application of cisplatin is the acquired or intrinsic drug resistance exhibited by some tumors. In the present study, we have assessed the potential of an intracellular energy balancing system as a target for augmentation of cisplatin sensitivity in tumors. AMP-activated protein kinase (AMPK) regulates the energy balance system by monitoring intracellular energy status. Here we demonstrate that AMPK is rapidly activated by cisplatin in AGS and HCT116 cancer cells. The inhibition of AMPK in those cells and in xenografts of HCT116 resulted in a remarkable increase in cisplatin-induced apoptosis, which was associated with hyper-induction of the tumor suppressor p53. We further showed that ERK, but not ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) kinases, was involved in the hyper-induction of p53 by the inhibition of cisplatin-induced AMPK. By way of contrast, cisplatin did not induce AMPK activation in HeLa cells, which appear to have a relatively high sensitivity to cisplatin-induced cytotoxicity, but expression of the constitutive active form of AMPK in HeLa cells resulted in a significant increase of cell viability after cisplatin treatment. Collectively, our data suggest that AMPK performs a pivotal function for protection against the cytotoxic effect of cisplatin, thereby implying that AMPK is one of the cellular factors determining the cellular sensitivity to cisplatin. On the basis of these observations, we propose that a strategy combining cisplatin and AMPK inhibition could be developed into a novel chemotherapeutic modality.