Ectopic ATP Synthase Blockade Suppresses Lung Adenocarcinoma Growth by Activating the Unfolded Protein Response
Ectopic ATP Synthase Blockade Suppresses Lung Adenocarcinoma Growth by Activating the Unfolded Protein Response
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DOI：
10.1158/0008-5472.can-12-0567
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发表时间：
2012-09-15
期刊：
影响因子：
11.2
通讯作者：
Juan, Hsueh-Fen
中科院分区：
文献类型：
--
作者：
Chang, Hsin-Yi;Huang, Hsuan-Cheng;Juan, Hsueh-Fen
线粒体F1F0-ATP合酶在质膜上的异位表达已被报道在癌症中发生，但它是否在这一背景下发挥功能尚不清楚。在这里，我们发现在肺腺癌细胞的间歇性分布中，异位ATP合成酶和电子转移链存在于细胞膜上，这是支持癌细胞增殖的关键。应用三磷酸腺苷合成酶抑制剂黄绿色素能诱导肺癌细胞周期停滞，抑制肺癌细胞的增殖和非贴壁生长。对黄绿色素处理后蛋白质表达谱的分析表明，该化合物诱导了与翻译起始因子2α(eIF2α)磷酸化相关的未折叠蛋白反应(UPR)，触发了细胞生长抑制。Citreoviridin增强的eIF2α的磷酸化可以通过siRNA介导的UPR激酶PKR样内质网状激酶(PERK)的减弱和抗氧化剂N-乙酰半胱氨酸的处理来逆转，从而证实在Citreoviridin处理后，ROS促进了UPR。因此，UPR和ROS的协同升高启动了一个正反馈循环，从而一致地阻止了细胞的增殖。我们的发现确定了肺癌细胞质膜异位ATP合成酶的分子功能，并促使进一步研究其抑制作为一种潜在的治疗方法。癌症资源；72(18)；4696-706。(C)2012年AACR。
Ectopic expression of the mitochondrial F1F0-ATP synthase on the plasma membrane has been reported to occur in cancer, but whether it exerts a functional role in this setting remains unclear. Here we show that ectopic ATP synthase and the electron transfer chain exist on the plasma membrane in a punctuated distribution of lung adenocarcinoma cells, where it is critical to support cancer cell proliferation. Applying ATP synthase inhibitor citreoviridin induced cell cycle arrest and inhibited proliferation and anchorage-independent growth of lung cancer cells. Analysis of protein expression profiles after citreoviridin treatment suggested this compound induced the unfolded protein response (UPR) associated with phosphorylation the translation initiation factor 2 alpha (eIF2 alpha), triggering cell growth inhibition. Citreoviridin-enhanced eIF2 alpha phosphorylation could be reversed by siRNA-mediated attenuation of the UPR kinase PKR-like endoplasmic reticulum kinase (PERK) combined with treatment with the antioxidant N-acetylcysteine, establishing that reactive oxygen species (ROS) boost UPR after citreoviridin treatment. Thus, a coordinate elevation of UPR and ROS initiates a positive feedback loop that convergently blocks cell proliferation. Our findings define a molecular function for ectopic ATP synthase at the plasma membrane in lung cancer cells and they prompt further study of its inhibition as a potential therapeutic approach. Cancer Res; 72(18); 4696-706. (C) 2012 AACR.