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[Impact of HSP90 Inhibition on Viability and Cell Cycle in Relation to p53 Status]
Background:
Chaperone system inhibition is a recent promising strategy for cancer treatment that exploits increased metabolic needs required for rapid proliferation as well as higher level of proteotoxic stress in neoplastic cells. Chaperone HSP90 plays a key role in proper folding of many de novo synthesized proteins, so-called clients, including tumor suppressor p53 which is commonly mutated in majority of cancers. Aim of this work was therefore to understand the impact of HSP90 inhibition by NVP-AUY922 on breast cancer cell lines with wild-type and mutated p53.
Methods:
Flow cytometry was used to analyze cell viability by fluorescein diacetate assay and changes in cell cycle. Western blotting was used to analyze expression of p53 and p21 proteins.
Results:
Analysis of cell viability after HSP90 inhibition revealed higher sensitivity of cell line with wild-type p53. Cell cycle analysis then showed that both cell lines undergo increase in G2/M block of the cell cycle, but wild-type cell line had also substantial decrease in proliferative capacity of treated cells. We also observed increased expression of negative cell cycle regulator p21 in cell line with wild-type p53.
Conclusions:
Since p21 is directly regulated by p53, our results suggest that mutation status of p53 can be important factor in treatment of breast cancer cells by HSP90 chaperone inhibition and that wild-type p53 can increase sensitivity to HSP90 inhibition.Key words: breast cancer - cell cycle - chaperone - HSP90 - TP53 - p21 - p53 - NVP-AUY922This work was supported by the project MEYS - NPS I - LO1413.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 6. 5. 2016Accepted: 17. 5. 2016.
Insights
HSP90 inhibition by NVP-AUY922 shows that wild-type p53 increases breast cancer cell sensitivity. This chaperone inhibition impacts cell cycle regulation, particularly in cells with wild-type p53.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Chaperone system inhibition, specifically targeting HSP90, is a promising cancer treatment strategy.
- HSP90 is crucial for folding client proteins, including tumor suppressor p53, which is frequently mutated in cancers.
- Neoplastic cells exhibit increased metabolic demands and proteotoxic stress, making them vulnerable to chaperone inhibition.
Purpose of the Study:
- To investigate the impact of HSP90 inhibition using NVP-AUY922 on breast cancer cell lines.
- To compare the effects in cell lines with wild-type versus mutated p53.
- To understand the role of p53 mutation status in response to HSP90 inhibition.
Main Methods:
- Cell viability was assessed using flow cytometry and fluorescein diacetate assay.
- Cell cycle progression was analyzed via flow cytometry.
- Protein expression of p53 and p21 was evaluated using Western blotting.
Main Results:
- Breast cancer cell lines with wild-type p53 exhibited higher sensitivity to HSP90 inhibition by NVP-AUY922.
- Both cell lines showed an increased G2/M block in the cell cycle; however, wild-type p53 lines also displayed a significant reduction in proliferative capacity.
- Increased expression of the cell cycle regulator p21 was observed in wild-type p53 cell lines.
Conclusions:
- The p53 mutation status is a critical factor in the response of breast cancer cells to HSP90 chaperone inhibition.
- Wild-type p53 status appears to enhance sensitivity to HSP90 inhibition, potentially mediated by p21 regulation.
- Targeting HSP90 offers a potential therapeutic avenue, with p53 status guiding treatment efficacy.
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