Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by activating the unfolded protein response

Hsin Yi Chang, Hsuan Cheng Huang, Tsui Chin Huang, Pan Chyr Yang, Yi Ching Wang, Hsueh Fen Juan

研究成果: Article同行評審

53 引文 斯高帕斯(Scopus)


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 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.

頁(從 - 到)4696-4706
期刊Cancer Research
出版狀態Published - 2012 九月 15

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究


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