7月20日,，Cancer Research雜志在線報道，抑制異位表達在肺腺癌細胞膜上的ATP合成酶可誘導未折疊蛋白反應,，從而觸發(fā)細胞生長抑制,。
科學家早已發(fā)現癌癥細胞膜上存在線粒體F1F0-ATP合酶的異位表達，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,，異位表達的ATP合成酶和電子傳遞鏈在肺腺癌細胞膜上存在間斷性分布,，這對于支持癌細胞增殖是關鍵的。應用ATP合酶抑制劑黃綠青霉素,，可誘導細胞周期阻滯和抑制肺癌細胞的增殖和不依賴于細胞錨定的肺癌細胞增長,。
黃綠青霉素治療后，蛋白質表達譜的分析表明,，這種化合物能誘導未折疊蛋白反應（UPR）,，并伴隨著磷酸化翻譯起始因子2α（eIF2α），從而觸發(fā)細胞生長抑制,。黃綠青霉素增強eIF2α蛋白磷酸化,，可被siRNA介導的UPR激酶PERK下調和抗氧化劑N-乙酰半胱氨酸聯合治療所逆轉。這說明,，黃綠青霉素治療后,，活性氧（ROS）促進了UPR。因此,，UPR和活性氧協(xié)同升高啟動了一個正反饋循環(huán),，最終阻止細胞增殖。
該研究結果確定了在肺癌細胞膜異位表達的ATP合酶的分子功能,，為進一步研究以此為靶點的治療方法打下了良好的基礎,。（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.
