Chang, Hsin-YiHsin-YiChangHuang, Hsuan-ChengHsuan-ChengHuangHuang, Tsui-ChinTsui-ChinHuangPAN-CHYR YANGWang, Yi-ChingYi-ChingWangJuan, Hsueh-FenHsueh-FenJuan2020-12-022020-12-0220120008-5472https://www.scopus.com/inward/record.uri?eid=2-s2.0-84866355221&doi=10.1158%2f0008-5472.CAN-12-0567&partnerID=40&md5=b51aba32ec584fa0a998cdedc37ed194https://scholars.lib.ntu.edu.tw/handle/123456789/523590Ectopic 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. ?2012 AACR.[SDGs]SDG3acetylcysteine; adenosine triphosphatase inhibitor; citreoviridin; initiation factor 2alpha; phosphotransferase; PKR like endoplasmic reticulum kinase; proton transporting adenosine triphosphate synthase; reactive oxygen metabolite; small interfering RNA; unclassified drug; antineoplastic activity; apoptosis; article; cancer cell; cancer inhibition; cell cycle arrest; cell cycle G0 phase; cell cycle G1 phase; cell proliferation; controlled study; drug cytotoxicity; electron transport; feedback system; human; human cell; lung adenocarcinoma; priority journal; protein analysis; protein expression; protein phosphorylation; protein protein interaction; proteomics; unfolded protein response; Adenocarcinoma; Blotting, Western; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Flow Cytometry; Fluorescent Antibody Technique; Humans; Lung Neoplasms; Mitochondrial Proton-Translocating ATPases; RNA, Small Interfering; Transfection; Unfolded Protein Responsejournal article10.1158/0008-5472.CAN-12-0567228220832-s2.0-84866355221