Simvastatin functions as a heat shock protein 90 inhibitor against triple‐negative breast cancer

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.

STAT3 and mutp53 Engage a Positive Feedback Loop Involving HSP90 and the Mevalonate Pathway

“…Therefore, based on this and previous studies, STAT3 can be consider at the center of a hub crucial for the control of tumorigenesis (Figure 6). Indeed, STAT3 activation sustains the interplay between HSP90 and the mevalonate cascade, according to previous studies showing that HSF1 sustained the mevalonate pathway (35), that HSP90 sustained SREBP activation (36) and that Simvastatin inhibited HSP90 (37). Of note, STAT3 can be activated by several cytokines including VEGF, whose production is promoted by STAT3 activation (38) and also by mutp53 due to its interaction with NFkB (13).…”

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

“…In breast cancer stem-like cells, statins at non-toxic doses significantly alter a shared cluster of 37 genes, including the Hippo, Notch, and Wnt pathways, to hold back EMT processes ( 155 ). Simvastatin induces breast cancer cell death through the deactivation of PI3K/Akt and MAPK/Erk signals ( 156 ) and also prevents triple-negative breast cancer proliferation and metastasis through Foxo3a phosphorylation ( 157 ) or HSP90 acetylation ( 158 ). Another statin, pitavastatin, can slow breast cancer-induced bone metastasis and reduce urine-derived volatile organic compounds through the mevalonate pathway ( 159 ).…”

Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights

“…The clinical focus is currently heading towards tailored therapy to characterise more targets with highly unprecedented approaches 11 . A number of investigational therapies such as heat shock protein 90 alpha (HSP90α) inhibitors, autophagy inducers, and PI3K-AKT-mTOR pathway inhibitors could hold promise 12 , 13 .…”