Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells

Abstract

BackgroundHeat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo.ResultsIn this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition.ConclusionThese results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.

Nanoparticles for Bioapplications: Study of the Cytotoxicity of Water Dispersible Quantum Dots

“…AAG is an anti-tumour drug that inhibits the activity of Hsp90, a protein necessary for the growth of the cells [62,63]. The cytotoxicity results showed that CdSe(S) QDs inhibit the cell viability by 64.4±0.5% at a concentration of 500 µg/ml; a similar value to that of 17-AAG (66.4±2.7%) at a concentration of only 0.06 µg/ml ( Figure 5).…”

“…In addition, 50% of cancer cells, including HCT-116, depend upon a heat-shock protein (such as Hsp90) to survive [61]. The viability of these cancer cells decreases in the presence of Hsp90 inhibitor 17-AAG, which is a common antitumour compound [62,63]. The viability of HCT-116 cells was therefore investigated both in the presence of 17-AAG and after treatment of the cells with QDs.…”

Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins

“…Therefore, it is likely that many of the activities of Hop in cancer are linked to perturbations in the function of the Hsp70/Hsp90 complex. This conclusion is supported by the observations that compounds that disrupt interactions between Hop and the Hsp90 or Hsp70 chaperone are toxic to cancer cells (Horibe et al 2011;Horibe et al 2012).…”

“…A hybrid peptide comprising a sequence based on the TPR2A region of Hop was designed to competitively inhibit the interaction between Hsp90 and Hop (Horibe et al 2011). This peptide induced cell death in a range of cancer cell lines in vitro, as well as displaying anti-tumour activity in a pancreatic cancer xenograft model (Horibe et al 2012). The compound also showed differential toxicity in that it did not affect the viability of normal cells, which might be attributed to the constitutive formation of the Hsp90 complex in cancer cells as opposed to normal cells (Barrott and Haystead 2013;Jego et al 2013).…”

Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival

“…20,21,24 Furthermore, it has also been shown that specific inhibitors 32 or a competitor peptide for the Hsp90-HOP 33 interaction inhibit tumor development, pointing to the Hsp90-HOP complex as a potentially selective anticancer therapeutic target. 33,34 Mechanistically, secreted HOP 35 carried by exosome-like extracellular vesicles 11 may promote PrP C -dependent proliferation via activation of PI3K and ERK1/2 7 or by binding to activin A receptor, type II-like kinase-2 and activating the SMAD-ID signaling. 26 Remarkably, our results demonstrate that PrP C is expressed in U87 cells and that its knockdown decreases proliferation in xenografted tumors and increases animal survival.…”