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Simvastatin functions as a heat shock protein 90 inhibitor against triple‐negative breast cancer
- Source :
- Cancer Science
- Publication Year :
- 2018
- Publisher :
- John Wiley and Sons Inc., 2018.
-
Abstract
- Acetylation plays an important role in regulating the chaperone activity of heat shock protein 90 (Hsp90) during malignant transformation through the stabilization and conformational maturation of oncogenic proteins. However, the functional acetylation sites, potential anticancer drug targets, are still emerging. We found that acetylation at K292 in Hsp90α is critical for the development and treatment of breast cancer. Acetylation at K292 not only augments the affinity of Hsp90 to ATP, cochaperones, and client proteins but it also promotes cancer cell colony formation, migration, and invasion in vitro as well as tumor growth in vivo. Importantly, K292-acetylated Hsp90 has been validated as an exciting anticancer drug target by interfering with the complex formation between K292-acetylated Hsp90 and cochaperone Cdc37, leading to diminishment of kinase client maturation and proteasome-dependent degradation of kinase substrates. Furthermore, we showed that simvastatin prevented, whereas LBH589 promoted, the progression of Hsp90 chaperone cycling and client maturation, resulting in an increment of cell apoptosis by the combination of simvastatin and LBH589 in a mouse xenograft model. These data suggest that simvastatin is a novel Hsp90 inhibitor to disrupt the formation of the K292-acetylated Hsp90/Cdc37 complex in triple-negative breast cancer cells. The combination of simvastatin with LBH589 could be used as a novel therapeutic strategy for triple-negative breast cancer.
- Subjects :
- 0301 basic medicine
Cancer Research
Simvastatin
Indoles
Chaperonins
Apoptosis
Cell Cycle Proteins
Triple Negative Breast Neoplasms
Hydroxamic Acids
Hsp90 inhibitor
Mice
0302 clinical medicine
Adenosine Triphosphate
Antineoplastic Combined Chemotherapy Protocols
Panobinostat
polycyclic compounds
Triple-negative breast cancer
Mice, Inbred BALB C
biology
Chemistry
LBH589
General Medicine
Hsp90
Cdc37
Oncology
CDC37
030220 oncology & carcinogenesis
Original Article
Female
medicine.drug
Protein Binding
Mice, Nude
03 medical and health sciences
Heat shock protein
Cell Line, Tumor
medicine
Animals
Humans
HSP90 Heat-Shock Proteins
acetylation
Lysine
Original Articles
Xenograft Model Antitumor Assays
030104 developmental biology
Drug Discovery and Delivery
Acetylation
Cancer cell
Cancer research
biology.protein
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 13497006 and 13479032
- Volume :
- 109
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Cancer Science
- Accession number :
- edsair.doi.dedup.....e5d42017146e26ab7510c750bca64119