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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Lipid-peroxidation; Carcinoma; Mitotane; Cancer; Steroidogenesis; Ketoconazole; Mechanisms; Pathways; Mitochondria; Stimulation
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Zeitschrift Cell Death & Disease
Quellenangaben Band: 11, Heft: 3, Seiten: , Artikelnummer: 192 Supplement: ,
Verlag Nature Publishing Group
Verlagsort Macmillan Building, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Analytical Pathology (AAP)