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Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis.

  • Belavgeni A Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Bornstein SR Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • von Mässenhausen A Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Tonnus W Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Stumpf J Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Meyer C Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Othmar E Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Latk M Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Kanczkowski W Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Kroiss M Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, 97080 Würzburg, Germany.
  • Hantel C Clinic of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich, 8091 Zurich, Switzerland.
  • Hugo C Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Fassnacht M Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, 97080 Würzburg, Germany.
  • Ziegler CG Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Schally AV Veterans Affairs (VA) Medical Center, Miami, FL 33125; andrew.schally@va.gov andreas.linkermann@ukdd.de.
  • Krone NP Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
  • Linkermann A Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; andrew.schally@va.gov andreas.linkermann@ukdd.de.
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  • 2019-10-16
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2019
adrenal
adrenocortical carcinoma
endocrine tumors
ferroptosis
regulated necrosis
3T3 Cells
Adrenal Cortex Neoplasms
Adrenocortical Carcinoma
Animals
Apoptosis
Ferroptosis
HEK293 Cells
HT29 Cells
Humans
Insulin
Iron
Linoleic Acid
Mice
Mitotane
Phospholipid Hydroperoxide Glutathione Peroxidase
Selenium
Sermorelin
Transferrin
English 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.
Language
  • English
Open access status
bronze
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https://sonar.ch/global/documents/88500
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