@article{SiebertCiatoMurakamietal.2019,
  author    = {Siebert, Claudia and Ciato, Denis and Murakami, Masanori and Frei-Stuber, Ludwig and Perez-Rivas, Luis Gustavo and Monteserin-Garcia, Jos{\´e} Luis and N{\"o}lting, Svenja and Maurer, Julian and Feuchtinger, Annette and Walch, Axel K. and Haak, Harm R. and Bertherat, J{\´e}r{\^o}me and Mannelli, Massimo and Fassnacht, Martin and Korpershoek, Esther and Reincke, Martin and Stalla, G{\"u}nter K. and Hantel, Constanze and Beuschlein, Felix},
  title     = {Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma},
  series = {Frontiers in Endocrinology},
  volume    = {10},
  journal   = {Frontiers in Endocrinology},
  doi       = {10.3389/fendo.2019.00487},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238029},
  year      = {2019},
  abstract  = {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 toward ACC.},
  language  = {en}
}
@article{WeigandRonchiRizkRabinetal.2017,
  author    = {Weigand, Isabel and Ronchi, Cristina L. and Rizk-Rabin, Marthe and Dalmazi, Guido Di and Wild, Vanessa and Bathon, Kerstin and Rubin, Beatrice and Calebiro, Davide and Beuschlein, Felix and Bertherat, J{\´e}r{\^o}me and Fassnacht, Martin and Sbiera, Silviu},
  title     = {Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  number    = {49},
  doi       = {10.1038/s41598-017-00125-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157952},
  year      = {2017},
  abstract  = {Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40\% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion.},
  language  = {en}
}