Molecular mechanisms of ferroptosis and its effects on bladder cancer

Abstract

Bladder cancer (BC) is one of the 3 common malignant tumors in the urinary system, with high incidence, easy metastasis, poor therapeutic efficacy, and poor prognosis, which seriously threatens the health of human. Tumor cells exhibit a strong demand for iron, and iron overload can induce ferroptosis, which is an iron dependent cell death caused by lipid peroxidation and cell membrane damage. Therefore, ferroptosis has strong anti-tumor potential. The molecular mechanisms of ferroptosis is associated with abnormalities in cellular phospholipid metabolism and iron metabolism, and dysregulation of antioxidant and non-antioxidant systems Xc^-/glutathione (GSH)/glutathione peroxidase 4 (GPX4). Ferroptosis relevant molecules play important roles in the occurrence and development, metastasis, drug resistance, and immune response of BC, and are expected to become targets for the treatment of BC.

Keywords: Xc-/glutathione/glutathione peroxidase 4; bladder cancer; ferroptosis; ferroptosis relevant molecules; iron metabolism; lipid peroxidation; phospholipid metabolism.

图1

铁死亡的经典分子通路 Figure 1 Classical molecular pathway of ferroptosis PUFA: Polyunsaturated fatty acids; MUFA: Mono-unsaturated fatty acids; LDs: Lipid droplets; YAP: Yes-associated protein; TEAD: Transcriptional enhancer activator domain; ACSL: Acyl-coenzyme A synthetase long chain family member; LPCAT3: Lysophosphatidyl acyltransferase 3; TF: Transferrin; TfR: Transferrin receptor; LIP: Labile iron pool; ALOX: Arachidonate lipoxygenase; FPN1: Ferroportin 1; GSH: Glutathione; GPX4: Glutathione peroxidase 4; ROS: Reactive oxygen species; PLOOH: Phospholipid hydroperoxides; CoQ: Coenzyme Q; BH4: Tetrahydrobioterin; TP53: Tumor protein 53; HSPA5: Heat shock protein family A member 5; SLC7A11: Solute carrier family 7 member 11; SLC3A2: Solute carrier family 3 member 2; NRF2: Nuclear factor E2-related factor 2; ESCRT-III: Endosomal sorting complex required for transport-III.