Journal
CANCER RESEARCH
Volume 72, Issue 18, Pages 4696-4706Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-12-0567
Keywords
-
Categories
Funding
- National Research Program for Genomic Medicine [NSC 100-3112-B-002-011]
- National Science Council of Taiwan [NSC 97-2311-B-002-010-MY3, NSC 99-2621-B-002-005-MY3]
- National Taiwan University Cutting-Edge Steering Research Project [10R70602C3]
- National Health Research Institutes, Taiwan [NHRI-EX98-9819PI]
Ask authors/readers for more resources
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 2 alpha (eIF2 alpha), triggering cell growth inhibition. Citreoviridin-enhanced eIF2 alpha 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. Cancer Res; 72(18); 4696-706. (C) 2012 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available