Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells
H-Y Chang1, T-C Huang2, N-N Chen3
1Department of Life Science, National Taiwan University, Taipei, Taiwan.
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.
Insights
ATP synthase inhibitors like citreoviridin show promise against breast cancer by halting cell growth. Combining citreoviridin with bortezomib enhances this effect, inducing a unique cell death pathway.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- F1Fo ATP synthase is crucial for cellular energy production, primarily in mitochondria.
- Ectopic expression of ATP synthase and electron transport chain complexes on breast cancer cells presents a novel therapeutic target.
Purpose of the Study:
- To investigate the anticancer effects of the ATP synthase inhibitor citreoviridin on breast cancer.
- To explore the synergistic effects of combining citreoviridin with the proteasome inhibitor bortezomib.
Main Methods:
- Proteomic analysis to identify differentially expressed proteins.
- Investigated the role of PERK-mediated eIF2α phosphorylation in citreoviridin's mechanism.
- Assessed cell cycle progression, protein synthesis, and cell death pathways.
Main Results:
- Citreoviridin induced cell cycle arrest at G0/G1 by attenuating protein synthesis via PERK-mediated eIF2α phosphorylation.
- Combined treatment with bortezomib enhanced endoplasmic reticulum (ER) stress, counteracted cyclin D3 compensation, and led to CDK1 deactivation and PCNA downregulation.
- The combination therapy resulted in non-apoptotic, caspase- and autophagy-independent cell death characterized by cytoplasmic vacuolization.
Conclusions:
- Citreoviridin effectively inhibits breast cancer cell proliferation by disrupting cell cycle progression.
- Combination therapy with bortezomib potentiates anticancer activity by amplifying ER stress and inducing a unique cell death mechanism.
- Targeting ATP synthase and proteasome pathways offers a promising therapeutic strategy for breast cancer.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:57Targeted Cancer Therapies
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:38Mitogens and the Cell Cycle
02:56Treatment Resistant Cancers
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase