Ectopic expression of the mitochondrial F(1)F(0)-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.