Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma

Please always quote using this URN: urn:nbn:de:bvb:20-opus-238029
  • 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 HSP90Background: 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 HSP90β. Within a cohort of ACC patients, HSP90β 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.show moreshow less

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Author: Claudia Siebert, Denis Ciato, Masanori Murakami, Ludwig Frei-Stuber, Luis Gustavo Perez-Rivas, José Luis Monteserin-Garcia, Svenja Nölting, Julian Maurer, Annette Feuchtinger, Axel K. Walch, Harm R. Haak, Jérôme Bertherat, Massimo Mannelli, Martin Fassnacht, Esther Korpershoek, Martin Reincke, Günter K. Stalla, Constanze Hantel, Felix Beuschlein
URN:urn:nbn:de:bvb:20-opus-238029
Document Type:Journal article
Faculties:Medizinische Fakultät / Medizinische Klinik und Poliklinik I
Language:English
Parent Title (English):Frontiers in Endocrinology
Year of Completion:2019
Volume:10
Article Number:487
Source:Frontiers in Endocrinology (2019) 10:487. https://doi.org/10.3389/fendo.2019.00487
DOI:https://doi.org/10.3389/fendo.2019.00487
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:C-terminal HSP90 inhibitors; N-terminal HSP90 inhibitors; adrenal gland; cortisol; prognostic marker
Release Date:2024/07/25
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International