Elucidating the Molecular Mechanisms of Ectopic ATP Synthase Blockade in Lung Cancer Cells

• Main Authors: Hsin-Yi Chang, 張心儀
• Other Authors: Hsueh-Fen Juan
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/36992430276964985771

博士 === 國立臺灣大學 === 分子與細胞生物學研究所 === 101 === Lung cancer is the leading cause of cancer-related death worldwide. Although targeted therapies can initiate dramatic clinical responses and offer significant therapeutic benefits and fewer side effects, the effectiveness of targeted therapies is currently limited because the majority of patients develop resistance over time, resulting in a relapse or worsening of the cancer. Thus, discovery of novel therapeutic markers might achieve the unmet clinical need. Ectopic expression of the mitochondrial F1Fo-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 transport chain exist in a punctuated distribution on the plasma membrane 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 of 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 reveal a molecular function for ectopic ATP synthase on the plasma membrane in lung cancer cells and prompt further study of its inhibition as a potential therapeutic application.