PuSH - Publication Server of Helmholtz Zentrum München: Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

Weigand, I.* ; Schreiner, J.* ; Röhrig, F.* ; Sun, N. ; Landwehr, L.S.* ; Urlaub, H.* ; Kendl, S.* ; Kiseljak-Vassiliades, K.* ; Wierman, M.E.* ; Angeli, J.P.F.* ; Walch, A.K. ; Sbiera, S.* ; Fassnacht, M.* ; Kroiss, M.*

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction.

Cell Death Dis. 11:192 (2020)

Publ. Version/Full Text

Research data

DOI

PMC

	Open Access Gold

Abstract
Metrics
Extra information

Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an iron-dependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC50 values of 5.7 x 10(-8), 8.1 x 10(-7) and 2.1 x 10(-8) M, respectively, while all non-steroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Lipid-peroxidation; Carcinoma; Mitotane; Cancer; Steroidogenesis; Ketoconazole; Mechanisms; Pathways; Mitochondria; Stimulation

ISSN (print) / ISBN 2041-4889

e-ISSN 2041-4889

Journal Cell Death & Disease

Quellenangaben Volume: 11, Issue: 3, Article Number: 192

Publisher Nature Publishing Group

Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Analytical Pathology (AAP)