Crosstalk between ferroptosis and steroid hormone signaling in gynecologic cancers

Abstract

Ferroptosis is a novel types of regulated cell death and is widely studied in cancers and many other diseases in recent years. It is characterized by iron accumulation and intense lipid peroxidation that ultimately inducing oxidative damage. So far, signaling pathways related to ferroptosis are involved in all aspects of determining cell fate, including oxidative phosphorylation, metal-ion transport, energy metabolism and cholesterol synthesis progress, et al. Recently, accumulated studies have demonstrated that ferroptosis is associated with gynecological oncology related to steroid hormone signaling. This review trends to summarize the mechanisms and applications of ferroptosis in cancers related to estrogen and progesterone, which is expected to provide a theoretical basis for the prevention and treatment of gynecologic cancers.

Keywords: estrogen; ferroptosis; gynecologic cancers; lipid peroxidation; progesterone.

FIGURE 1

Regulation mechanisms of estrogen and progesterone on ferroptosis in gynecologic cancers. Ferroptosis is driven by iron-dependent lipid peroxidation. There are multiple molecular mechanisms involved in the regulation of ferroptosis. Iron-loaded TF-TFRC complexes releases Fe²⁺ into the cytoplasm via SLC11A2. The intracellular free iron is stored as Fe³⁺-ferritin complex. The autophagy-dependent ferritinophagy is mediated by NCOA4 for degradation of ferritin at lysosome to release Fe²⁺. The excess Fe²⁺ induces lipid peroxidation via Fenton reaction. PUFAs, which are mainly from ACAC-mediated fatty acid synthesis or by the lipophagy, also can induce ferroptosis. PUFAs convert to PUFA-PL by ACSL4 and LPCAT3, finally induce lipid peroxidation. The system xc−-GSH-GPX4 pathway mainly acts as a defense system so as to antiferroptosis. In this pathway, cystine enters the cell and is oxidized to cysteine, with the action of GCL and GSS, GSH is synthesized and catalyzed by GPX4 to antiferroptosis. IPP, a metabolic intermediate from MVA pathway related to cholesterol synthesis, can enhance GPX4 activity and cause antiferroptotic effect. Transsulfuration pathway, GCH1-BH4 pathway and AIFM 2-CoQ10 pathway also have unique mechanisms to antiferroptosis. Estrogen binds to ESR and reduces free iron by inhibition of TFRC and ferritin or by promotion of ferroportin. Estrogen can also suppress lipid peroxidation through Wnt/β-catenin pathway. Progesterone enhances lipid peroxidation via its receptor PR-A. The other progesterone receptor PGRMC1 also mediated lipophagy to increase ROS generation. Both estrogen and progesterone supplement can inhibit cholesterol synthesis, which regulates GPX4 in turn.

FIGURE 2

The relationship between ferroptosis and the synthesis of estrogen and progesterone. The synthesis of estrogen and progesterone depends on cholesterol. Three molecules of acetyl-CoA condense successively to form HMG-CoA. HMG-CoA is then reduced to MVA by HMGCR, and is further phosphorylated and decarboxylated to form IPP. IPP is condensed to produce squalene and then squalene forms lanosterol by the catalysis of endoplasmic reticulum cyclase and oxygenase, finally lanosterol is converted to cholesterol. Cholesterol enters into mitochondria and converts to pregnenolone by P450scc. Then 17-OH pregnenolone is converted to DHEA and finally forms estrogen.