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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2019.00487

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

 Claudia Siebert1,  Denis Ciato1, Masanori Murakami1,  Ludwig Frei-Stuber1,  Luis G. Perez-Rivas1, José L. Monteserin-Garcia2, Svenja Nölting1, Julian Maurer1, Annette Feuchtinger3,  Axel K. Walch3,  Harm R. Haak4, 5, 6, Jérôme Bertherat7,  Massimo Mannelli8,  Martin Fassnacht9, Esther Korpershoek10, Martin Reincke1,  Günter K. Stalla1, 11,  Constanze Hantel12, 13 and  Felix Beuschlein1, 12*
  • 1Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Germany
  • 2Max Planck Institute of Psychiatry (MPI), Germany
  • 3Research Unit Analytical Pathology, Helmholtz Centre Munich, German Research Center for Environmental Health, Germany
  • 4Department of Internal Medicine, Maxima Medical Centre, Netherlands
  • 5CAPHRI School for Public Health and Primary Care, Maastricht University, Netherlands
  • 6Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Centre, Netherlands
  • 7Département de Endocrinologie et Maladies Métaboliques, Hôpital Cochin, France
  • 8Department of Clinical Pathophysiology, Endocrine Unit, University of Florence, Italy
  • 9Division of Endocrinology and Diabetology, Department of Internal Medicine I, University Hospital of Wuerzburg, Germany
  • 10Department of Internal Medicine, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands
  • 11Other, Germany
  • 12Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich, Switzerland
  • 13Abteilung für Endokrinologie, Diabetes und Knochenkrankheiten, Medizinische Klinik und Poliklinik III, Technische Universität Dresden, Germany

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 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 towards ACC.

Keywords: adrenal gland, cortisol, N-terminal HSP90 inhibitors, C-terminal Hsp90 inhibitors, prognostic marker

Received: 17 Apr 2019; Accepted: 04 Jul 2019.

Edited by:

Vincenzo Pezzi, University of Calabria, Italy

Reviewed by:

Jean-Yves Scoazec, Institut Gustave Roussy, France
Alfredo Berruti, University of Brescia, Italy  

Copyright: © 2019 Siebert, Ciato, Murakami, Frei-Stuber, Perez-Rivas, Monteserin-Garcia, Nölting, Maurer, Feuchtinger, Walch, Haak, Bertherat, Mannelli, Fassnacht, Korpershoek, Reincke, Stalla, Hantel and Beuschlein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Felix Beuschlein, Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Bavaria, Germany, Felix.Beuschlein@usz.ch