Ferroptosis and its emerging role in esophageal cancer

Abstract

The occurrence and development of tumors involve a series of life activities of cells, among which cell death has always been a crucial part in the research of tumor mechanisms and treatment methods. Ferroptosis is a non-apoptotic form of cell death, which is characterized by lipid peroxidation accumulation and further cell membrane rupture caused by excessive production of intracellular oxygen free radicals dependent on iron ions. Esophageal cancer is one of the common digestive tract tumors. Patients in the early stage are mainly treated with surgery, and the curative effect is awe-inspiring. However, surgery is far from enough for terminal patients, and it is the best choice to combine radiotherapy and chemotherapy before the operation or during the perioperative period. Although the treatment plan for patients with advanced esophageal cancer is constantly being optimized, we are disappointed at the still meager 5-year survival rate of patients and the poor quality of life. A series of complex problems, such as increased chemotherapy drug resistance and decreased radiotherapy sensitivity of esophageal cancer cells, are waiting for us to tackle. Perhaps ferroptosis can provide practical and feasible solutions and bring new hope to patients with advanced esophageal cancer. The occurrence of ferroptosis is related to the dysregulation of iron metabolism, lipid metabolism, and glutamate metabolism. Therefore, these dysregulated metabolic participant proteins and signaling pathways are essential entry points for using cellular ferroptosis to resist the occurrence and development of cancer cells. This review first introduced the main regulatory mechanisms of ferroptosis. It then summarized the current research status of ferroptosis in esophageal cancer, expecting to provide ideas for the research related to ferroptosis in esophageal cancer.

Keywords: antioxidant system; esophageal cancer; ferroptosis; lipid peroxidation; non-coding RNA.

FIGURE 1

Process of ferroptosis. (A) In general, Reactive Oxygen Species (ROS) is generated by iron ions and hydrogen peroxide in cells through the Fenton reaction. ROS is removed under the action of the antioxidant system, inhibiting lipid peroxidation and thus avoiding ferroptosis. (B) When intracellular iron levels rise, excessive ROS will be produced. The antioxidant system is not enough to counteract the excessive ROS, so lipid peroxidation is not inhibited, and ferroptosis occurs. The figure modified from (Yan et al., 2021).

FIGURE 2

Production of Lipid Peroxide. (A) TF binds to TFRC and enters cells in the form of endosomes; (B) STEAP3 reduces Fe3+ to Fe2+, which is released into the cytoplasm by DMT1 to form labile iron pool; (C) Under the action of PCBP, the free iron is transferred to ferritin, which is composed of heavy chain FTH and light chain FTL, and has the activity of iron oxidase, oxidizing Fe2+ into Fe3+ and stores it; (D) Iron ion-mediated Fenton reaction; (E) Excessive iron ions are transported extracellularly by FPN1; (F) Mitochondrial ferritin; (G) Iron autophagy process; (H) Lipid peroxidation. The figure modified from (Dev and Babitt, 2017).

FIGURE 3

Antioxidant system. (A) Cystine/glutamate antitransporter; (B) Glutathione peroxidase 4; (C) FSP1/CoQ10; (D) Antioxidant system in mitochondria. The figure modified from (Anandhan et al., 2020).

FIGURE 4

Action mechanism and regulatory genes of NRF2. (A) KEAP1 binds to NRF2, and NRF2 initiates ubiquitination under a non-stress state; (B) The ubiquitination of NRF2 strengthens its degradation; (C) Depolymerization of KEAP1-NRF2 complex under oxidative stress; (D) NRF2 enters the nucleus and binds to ARE; (E) Iron ion metabolism-related gene; (F) Glutathione metabolism-related genes; (G) Other related genes. The figure modified from (Kerins and Ooi, 2018).