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Siebert, C.* ; Ciato, D.* ; Murakami, M.* ; Frei-Stuber, L.* ; Perez-Rivas, L.G.* ; Monteserin-Garcia, J.L.* ; Noelting, S.* ; Maurer, J.* ; Feuchtinger, A. ; Walch, A.K. ; Haak, H.R.* ; Bertherat, J.* ; Mannelli, M.* ; Fassnacht, M.* ; Korpershoek, E.* ; Reincke, M.* ; Stalla, G.K.* ; Hantel, C.* ; Beuschlein, F.*

Heat shock protein 90 as a prognostic marker and therapeutic target for adrenocortical carcinoma.

Front. Endocrin. 10:487 (2019)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC.Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines.Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90 beta. Within a cohort of ACC patients, HSP90 beta expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2-and AKT-pathways by luminespib and ganetespib treatment.Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Adrenal Gland ; Cortisol ; N-terminal Hsp90 Inhibitors ; C-terminal Hsp90 Inhibitors ; Prognostic Marker; Hsp90 Molecular Chaperone; European Network; Crystal-structure; Client Protein; Middle Domain; Inhibitor; Expression; Degradation; Sensitivity; Cancer
Language english
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 1664-2392
e-ISSN 1664-2392
Journal Frontiers in Endocrinology
Quellenangaben Volume: 10, Issue: , Pages: , Article Number: 487 Supplement: ,
Publisher Frontiers
Publishing Place Lausanne
Reviewing status Peer reviewed
Institute(s) Research Unit Analytical Pathology (AAP)
CF Pathology & Tissue Analytics (CF-PTA)
POF-Topic(s) 30205 - Bioengineering and Digital Health
30505 - New Technologies for Biomedical Discoveries
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-500390-001
A-630600-001
DOI 10.3389/fendo.2019.00487
WOS ID WOS:000476789900002
PubMed ID 31379752
Erfassungsdatum 2019-08-12
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