The chaperone system in cancer therapies: Hsp90

Abstract

The chaperone system (CS) of an organism is composed of molecular chaperones, chaperone co-factors, co-chaperones, and chaperone receptors and interactors. It is present throughout the body but with distinctive features for each cell and tissue type. Previous studies pertaining to the CS of the salivary glands have determined the quantitative and distribution patterns for several members, the chaperones, in normal and diseased glands, focusing on tumors. Chaperones are cytoprotective, but can also be etiopathogenic agents causing diseases, the chaperonopathies. Some chaperones such as Hsp90 potentiate tumor growth, proliferation, and metastasization. Quantitative data available on this chaperone in salivary gland tissue with inflammation, and benign and malignant tumors suggest that assessing tissue Hsp90 levels and distribution patterns is useful for differential diagnosis-prognostication, and patient follow up. This, in turn, will reveal clues for developing specific treatment centered on the chaperone, for instance by inhibiting its pro-carcinogenic functions (negative chaperonotherapy). Here, we review data on the carcinogenic mechanisms of Hsp90 and their inhibitors. Hsp90 is the master regulator of the PI3K-Akt-NF-kB axis that promotes tumor cell proliferation and metastasization. We discuss pathways and interactions involving these molecular complexes in tumorigenesis and review Hsp90 inhibitors that have been tested in search of an efficacious anti-cancer agent. This targeted therapy deserves extensive investigation in view of its theoretical potential and some positive practical results and considering the need of novel treatments for tumors of the salivary glands as well as other tissues.

Keywords: Akt; Chaperone system; Chaperonopathies; Hsp90; Molecular chaperone; NF-kB; Negative chaperonotherapy.

Fig. 1

Important components of the human chaperone system that play a role in carcinogenesis forming functional teams and networks. The Hsp70/DnaK, Prefoldin, Hsp90, and CCT teams (framed in blue) interact with one another in various ways forming functional networks to maintain protein homeostasis with the result being the production of fully functional protein molecules (Pr) and the removal of defective peptides (protein degradation machineries, e.g., the ubiquitin-proteasome system, other proteases, and autophagy mechanisms). Each team undergoes functional cycles with turnover and exchange of components as indicated by the red moon-shaped icon. For details see text, Fig. 3, and (Macario and Conway de Macario , ; Wandinger et al. ; Schopf et al. ; Dahiya and Buchner ; Biebl and Buchner ; Edkins and Boshoff ; Knowlton et al. ; Birbo et al. ; Johnson 2021)

Fig. 2

Immunohistochemistry of Hsp90 in salivary gland tissue. (a) normal salivary glands, (b) sialadenitis, (c) Warthin’s tumor, and (d) mucoepidermoid carcinoma. The chaperone appears stained brown, with differences between the specimens in quantity and distribution. Magnification x200

Fig. 3

Hsp90 molecular mechanisms and regulation of the NF-kB signaling pathway in cancer. Constitutive or inducible (flagellin, TNF-α, IL-1β, and phorbol ester (PMA)-activated) NF-kB pathway is initiated by activation of the IKK complex. Hsp90 with its co-chaperones Cdc37 and FKBP4 and oncogene ORAOV1-B bind and stabilize the complex by abrogating IKKα and IKKβ degradation by the ubiquitin-proteasome system. Hsp90 also modulates the kinase activity of IKKα and IKKβ. PHD3 is downregulated in cancer cells to impede its inhibitory effect on Hsp90 and IKKβ interaction (green arrow on the left of the PHD3 icon). In the TNF-α activated NF-kB (otherwise referred to as p50/p65 heterodimer) pathway, Hsp90 regulates the activity of RIP1 to stimulate IKK activation. In flagellin-activated NF-kB, Hsp90 plays a role in upregulating the expression of TLR5, the cell-surface receptor for flagellin. Upon activation of IKKβ, IkBα is phosphorylated and degraded by the 26 S proteasome, releasing p65 and allowing its translocation into the nucleus, with the aid of Hsp70/FKBP4 complex, to bind to the promoter region of specific regulatory genes, including: (1) the cell-cycle and proliferation genes survivin, cyclin D1, CDK6, and c-myc; (2) the pro-inflammatory genes CXCL1, CXCL2, CXCL3, CXCL10, PX3, IL6, HEBGF, IL23A, CCL20, CSF2, and TNFα; (3) the migration and invasion genes MMP2, MMP9, and CXCL8; (4) the EMT genes E-cadherin (E-Cad), vimentin (Vim), and ZEB1); and (5) the angiogenesis gene VEGF. E-cadherin expression is repressed by ORAVO1-B (green arrow on the left of the E-Cad icon). TNF-α is involved in a positive feedback loop (dotted line) that potentiates the activation of the TNF-α-NF-kB pathway. Hsp90 also regulates the activation of Akt that in turn activates the NF-kB pathway. Hsp90 stabilizes MDMX that suppresses p53 from inhibiting survivin. NF-kB activation together with p53 inhibition up-regulate survivin expression promoting cell survival. Survivin expression enhances cyclin D1 activation thus mediating proliferation of cancer cells. Chk1 activity is potentiated by Hsp90 to promote proliferation. Hsp90 modulates apoptosis in cancer cells not only by its actions on survivin, but by upregulating xIAP, and cIAP and by inhibiting cleaved caspase 3 (C-casp3). All these processes, together, render the tumor cell prone to growth, invasion of adjacent tissues, and metastasization