Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells
Journal
Cell Death & Disease
Journal Volume
5
Journal Issue
e1540
Date Issued
2014
Author(s)
Abstract
F1Fo ATP synthase is present in all organisms and is predominantly located on the inner membrane of mitochondria in eukaryotic cells. The present study demonstrated that ATP synthase and electron transport chain complexes were ectopically expressed on the surface of breast cancer cells and could serve as a potent anticancer target. We investigated the anticancer effects of the ATP synthase inhibitor citreoviridin on breast cancer cells through proteomic approaches and revealed that differentially expressed proteins in cell cycle regulation and in the unfolded protein response were functionally enriched. We showed that citreoviridin triggered PERK-mediated eIF2α phosphorylation, which in turn attenuated general protein synthesis and led to cell cycle arrest in the G0/G1 phase. We further showed that the combination of citreoviridin and the 26S proteasome inhibitor bortezomib could improve the anticancer activity by enhancing ER stress, by ameliorating citreoviridin-caused cyclin D3 compensation, and by contributing to CDK1 deactivation and PCNA downregulation. More interestingly, the combined treatment triggered lethality through unusual non-apoptotic caspase- and autophagy-independent cell death with a cytoplasmic vacuolization phenotype. The results imply that by boosting ER stress, the combination of ATP synthase inhibitor citreoviridin and 26S proteasome inhibitor bortezomib could potentially be an effective therapeutic strategy against breast cancer. ? 2014 Macmillan Publishers Limited All rights reserved.
SDGs
Other Subjects
bortezomib; citreoviridin; cyclin D3; initiation factor 2alpha; proton transporting adenosine triphosphate synthase inhibitor; purinergic receptor; unclassified drug; ATP dependent 26S protease; aurovertin; boronic acid derivative; bortezomib; calcium; caspase; citreoviridin; cyclin D3; initiation factor 2; PERK kinase; proteasome; proteasome inhibitor; protein kinase R; proton transporting adenosine triphosphate synthase; purinergic receptor; pyrazine derivative; ubiquitin; antineoplastic activity; Article; autophagy; breast cancer; calcium transport; cancer combination chemotherapy; cell cycle arrest; cell cycle progression; cell cycle regulation; cell death; cell proliferation; cell vacuole; colony forming cell; controlled study; down regulation; electron transport; endoplasmic reticulum stress; G1 phase cell cycle checkpoint; human; human cell; immunofluorescence; investigative procedures; membrane structure; mitochondrial membrane potential; phenotype; priority journal; protein degradation; protein expression; protein function; protein modification; protein phosphorylation; protein quaternary structure; protein synthesis; proteomics; real time polymerase chain reaction; two dimensional electrophoresis; unfolded protein response; Western blotting; antagonists and inhibitors; Breast Neoplasms; cell cycle checkpoint; cell membrane; drug effects; drug screening; enzymology; female; metabolism; molecularly targeted therapy; pathology; phosphorylation; tumor cell line; Eukaryota; Aurovertins; Autophagy; Boronic Acids; Bortezomib; Breast Neoplasms; Calcium; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cyclin D3; eIF-2 Kinase; Electron Transport; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Female; Humans; Mitochondrial Proton-Translocating ATPases; Molecular Targeted Therapy; Phosphorylation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Receptors, Purinergic; Tumor Stem Cell Assay; Ubiquitin; Unfolded Protein Response; Vacuoles
Publisher
Springer Nature
Type
journal article