Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration

Abstract

Glioblastoma multiforme (GBM) is one of the most common aggressive, resistant, and invasive primary brain tumors that share neurodegenerative actions, resembling many neurodegenerative diseases. Although multiple conventional approaches, including chemoradiation, are more frequent in GBM therapy, these approaches are ineffective in extending the mean survival rate and are associated with various side effects, including neurodegeneration. This review proposes an alternative strategy for managing GBM and neurodegeneration by targeting heat shock protein 90 (Hsp90). Hsp90 is a well-known molecular chaperone that plays essential roles in maintaining and stabilizing protein folding to degradation in protein homeostasis and modulates signaling in cancer and neurodegeneration by regulating many client protein substrates. The therapeutic benefits of Hsp90 inhibition are well-known for several malignancies, and recent evidence highlights that Hsp90 inhibitors potentially inhibit the aggressiveness of GBM, increasing the sensitivity of conventional treatment and providing neuroprotection in various neurodegenerative diseases. Herein, the overview of Hsp90 modulation in GBM and neurodegeneration progress has been discussed with a summary of recent outcomes on Hsp90 inhibition in various GBM models and neurodegeneration. Particular emphasis is also given to natural Hsp90 inhibitors that have been evidenced to show dual protection in both GBM and neurodegeneration.

Keywords: Hsp90; chemosensitivity; glioblastoma; neurodegenerations.

Figure 1

Structure and mechanism of Hsp90. (A) Residue mapping showing the structural domains of an Hsp90 monomer and the structure of an Hsp90 dimer. (B) General mechanism of Hsp90 in stabilizing and degrading client proteins (causative factors in GBM and NDDs). Client protein Hsp90 binding to the various client protein is facilitated by a conformational change in dimers induced by the binding of ATP in the NTD domain. Hsp90-targeted inhibitors compete with ATP and cause a release of client proteins leading to the degrading by the ubiquitin-proteasome degradation system. NTD, N-terminal domain; CL, charged linker region; MD, middle domain, CTD, C-terminal domain; ATP, adenosine triphosphate; GBM, glioblastoma multiforme; NDDs, neurodegenerative diseases.

Figure 2

Molecular mechanism of Hsp90 inhibition by natural products in GBM. Hsp90 client proteins play essential roles in GBM progression and maintenance. Targeting several signal transduction pathways that support GBM growth and survival can be facilitated when Hsp90 is inhibited, stimulating the degradation of Hsp90 client proteins by ubiquitin-proteasome systems.

Figure 3

Molecular mechanism of Hsp90 inhibition by natural products in alleviating neurodegeneration. Hsp90 inhibition by natural products could initiate two different processes, resulting in the degradation of client protein (pathological misfolded protein) and improving proteostasis. Hsp90 inhibition causes the release of pathogenic “client” proteins for proteasomal degradation, where the interaction of Hsp90 provides structural stability and maintenance of these client proteins. The inhibition of Hsp90 also stimulates the upregulation of other heat shock proteins via an HSF1-dependent mechanism. These HSPs can improve cell survival in a “stressed” environment by facilitating the clearance and blocking the accumulation of abnormal clients.

Figure 4

The chemical structures of naturally occurring Hsp90 inhibitors are pharmacologically active in GBM and neurodegeneration.