Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells

H. Y. Chang, T. C. Huang, N. N. Chen, H. C. Huang, H. F. Juan

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere1540
JournalCell Death and Disease
Volume5
Issue number11
DOIs
Publication statusPublished - Jan 1 2014

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Adenosine Triphosphate
Breast Neoplasms
Proteasome Inhibitors
Cyclin D3
Therapeutics
Unfolded Protein Response
Cell Cycle Resting Phase
Cell Cycle Proteins
Autophagy
Proliferating Cell Nuclear Antigen
G1 Phase
Eukaryotic Cells
Caspases
Electron Transport
Cell Cycle Checkpoints
Proteomics
Mitochondria
Cell Death
Down-Regulation
Phosphorylation

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells. / Chang, H. Y.; Huang, T. C.; Chen, N. N.; Huang, H. C.; Juan, H. F.

In: Cell Death and Disease, Vol. 5, No. 11, e1540, 01.01.2014.

Research output: Contribution to journalArticle

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