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

Abstract

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 irondependent 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 EC 50 values of 5.7 × 10 −8 , 8.1 × 10 −7 and 2.1 × 10 −8 M, respectively, while all nonsteroidogenic 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.

A Novel Ferroptosis-related 6-Gene Signature for Overall Survival Prediction in Patients with Thyroid carcinoma

“…Interestingly, GO and KEGG analyses both pointed out that the risk-related DEGs was correlated with hormone-metabolicrelated process, especially thyroid hormone. Weigand et al found that adrenal cortex cells are extraordinary sensitive to ferroptosis which depend on the active steroid synthetic pathways [40]. Another study [41] found that melatonin may be an excellent ferroptosis inhibitor and it can produce cerebroprotection from traumatic brain injury (TBI) by inhibiting neuronal Fth-mediated ferroptosis.…”

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

“…It has been observed that mitotane (30 and 50 μM) induced mitochondrial morphological alterations in human tumour adrenocortical cells (H295R and SW13), including membrane disruption, affecting respiratory chain enzymes, such as succinate dehydrogenase and the voltage‐dependent anion channel, resulting in the inhibition of tumour cell proliferation and induction of cellular apoptosis 75,76 . Although adrenal cortical cells were also susceptible to ferroptosis dependent on steroid pathways, mitotane did not induce this form of cell death in ACC cells 77 …”

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

“…There also exist some researches of the role of ferroptosis in endocrine gland disorders. Some studies, which examined the relationship between adrenal gland and ferroptosis, suggested that a adrenocortical cell-producing steroid presents a higher sensitivity to ferroptosis, compared to the non-steroidogenic adrenal medulla, when the GPX4 is suppressed, mainly because of its elevated expression of GPX4, ACSL4, adrenic and arachidonic acid, which are key regulators of ferroptosis (Weigand et al, 2020). Adrenocortical carcinomas (ACCs) are also sensitive to the induction of ferroptosis, and based on this result, a new therapeutic target to ACCs may present beyond the mitotane who cannot energize the ferroptosis pathway (Belavgeni et al, 2019).…”