7月20日,,Cancer Research雜志在線(xiàn)報(bào)道,,抑制異位表達(dá)在肺腺癌細(xì)胞膜上的ATP合成酶可誘導(dǎo)未折疊蛋白反應(yīng),,從而觸發(fā)細(xì)胞生長(zhǎng)抑制,。
科學(xué)家早已發(fā)現(xiàn)癌癥細(xì)胞膜上存在線(xiàn)粒體F1F0-ATP合酶的異位表達(dá),,但它是否在此情況下發(fā)揮功能性作用仍不清楚,。
本研究發(fā)現(xiàn),異位表達(dá)的ATP合成酶和電子傳遞鏈在肺腺癌細(xì)胞膜上存在間斷性分布,,這對(duì)于支持癌細(xì)胞增殖是關(guān)鍵的,。應(yīng)用ATP合酶抑制劑黃綠青霉素,可誘導(dǎo)細(xì)胞周期阻滯和抑制肺癌細(xì)胞的增殖和不依賴(lài)于細(xì)胞錨定的肺癌細(xì)胞增長(zhǎng),。
黃綠青霉素治療后,,蛋白質(zhì)表達(dá)譜的分析表明,,這種化合物能誘導(dǎo)未折疊蛋白反應(yīng)(UPR),并伴隨著磷酸化翻譯起始因子2α(eIF2α),,從而觸發(fā)細(xì)胞生長(zhǎng)抑制,。黃綠青霉素增強(qiáng)eIF2α蛋白磷酸化,可被siRNA介導(dǎo)的UPR激酶PERK下調(diào)和抗氧化劑N-乙酰半胱氨酸聯(lián)合治療所逆轉(zhuǎn),。這說(shuō)明,,黃綠青霉素治療后,活性氧(ROS)促進(jìn)了UPR,。因此,,UPR和活性氧協(xié)同升高啟動(dòng)了一個(gè)正反饋循環(huán),最終阻止細(xì)胞增殖,。
該研究結(jié)果確定了在肺癌細(xì)胞膜異位表達(dá)的ATP合酶的分子功能,,為進(jìn)一步研究以此為靶點(diǎn)的治療方法打下了良好的基礎(chǔ)。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by activating the unfolded protein response
Hsin-Yi Chang1,Hsuan-Cheng Huang2,Tsui-Chin Huang3,Pan-Chyr Yang4,Yi-Ching Wang5, andHsueh-Fen Juan
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 2α (eIF2α), triggering cell growth inhibition. Citreoviridin-enhanced eIF2α phosphorylation could be reversed by siRNA-mediated attenuation of the UPR 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.