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Ectopic ATP Synthase Blockade Suppresses Lung Adenocarcinoma Growth by Activating the Unfolded Protein Response
- Source :
- Cancer Research. 72:4696-4706
- Publication Year :
- 2012
- Publisher :
- American Association for Cancer Research (AACR), 2012.
-
Abstract
- 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. Cancer Res; 72(18); 4696–706. ©2012 AACR.
- Subjects :
- Cancer Research
medicine.medical_specialty
Lung Neoplasms
Blotting, Western
Fluorescent Antibody Technique
Adenocarcinoma
Transfection
Cell Line, Tumor
Internal medicine
medicine
Humans
RNA, Small Interfering
Lung cancer
Cell Proliferation
Lung
ATP synthase
biology
business.industry
Cell Membrane
Mitochondrial ATP Synthase
Mitochondrial Proton-Translocating ATPases
respiratory system
Flow Cytometry
medicine.disease
Blockade
Cell biology
Endocrinology
medicine.anatomical_structure
Oncology
Unfolded Protein Response
Unfolded protein response
biology.protein
business
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 72
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....a57564ff657bae393e1426d3ac0b77b3