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Belavgeni, A.* ; Bornstein, S.R. ; Krone, N.P. ; von Mässenhausen, A.* ; Tonnus, W.* ; Stumpf, J.* ; Meyer, C.* ; Othmar, E.* ; Latk, M.* ; Kanczkowski, W.* ; Kroiss, M.* ; Hantel, C.* ; Hugo, C.* ; Fassnacht, M.* ; Ziegler, C.G.* ; Linkermann, A.*

Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis.

Proc. Natl. Acad. Sci. U.S.A. 116, 22269-22274 (2019)
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Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Adrenal ; Ferroptosis ; Regulated Necrosis ; Endocrine Tumors ; Adrenocortical Carcinoma; Nonapoptotic Cell-death; Molecular-mechanisms; Regulated Necrosis; Metabolism; Pathways; Roles; Gpx4
Language english
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 116, Issue: 44, Pages: 22269-22274 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502600-001
G-502600-007
DOI 10.1073/pnas.1912700116
WOS ID WOS:000493720200049
Scopus ID 85074187786
PubMed ID 31611400
Erfassungsdatum 2019-10-17
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