title: Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells.
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.
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: T-C
authors.initials: TC
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: N-N
authors.initials: NN
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Huang
authors.affiliation: 1] Department of Life Science, National Taiwan University, Taipei, Taiwan [2] Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan [3] Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
authors.forename: H-F
authors.initials: HF
authors.lastname: Juan
mesh_terms: D001313:Aurovertins / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056743:Cyclin D3 / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011983:Receptors, Purinergic / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D001313:Aurovertins; D001897:Boronic Acids; D000069286:Bortezomib; D002118:Calcium; D020169:Caspases; D056743:Cyclin D3; D015852:Eukaryotic Initiation Factor-2; D025261:Mitochondrial Proton-Translocating ATPases; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011983:Receptors, Purinergic; D025801:Ubiquitin; D019892:eIF-2 Kinase; C061553:ATP dependent 26S protease; C014416:citreoviridin