Ferroptosis landscape in prostate cancer from molecular and metabolic perspective

Abstract

Prostate cancer is a major disease that threatens men's health. Its rapid progression, easy metastasis, and late castration resistance have brought obstacles to treatment. It is necessary to find new effective anticancer methods. Ferroptosis is a novel iron-dependent programmed cell death that plays a role in various cancers. Understanding how ferroptosis is regulated in prostate cancer will help us to use it as a new way to kill cancer cells. In this review, we summarize the regulation and role of ferroptosis in prostate cancer and the relationship with AR from the perspective of metabolism and molecular pathways. We also discuss the feasibility of ferroptosis in prostate cancer treatment and describe current limitations and prospects, providing a reference for future research and clinical application of ferroptosis.

Fig. 1. Metabolic pathways implicated in ferroptosis in prostate cancer.

Ferroptosis is mainly caused by iron-related lipid peroxidation, and the absorption, storage, utilization and export of iron in iron metabolism will affect ferroptosis. STAMP2-mediated ferric iron reduction and NCOA4-mediated ferritin autophagy can increase labile iron pools to sensitize cells to ferroptosis via the Fenton response. The classical inhibitory pathway of ferritin metabolism is mainly uptake of Cys by the cystine-glutamate antiporter (system xc⁻), which is used for the synthesis of GSH. GPX4 utilizes GSH as a cofactor to reduce lipid hydroperoxides to lipid alcohols. In addition, the activation of ACSL4, LPLAT5, and LOXs in the lipid metabolism pathway can promote the peroxidation of PUFA and induce ferroptosis. Conversely, the PI3K/AKT/mTOR pathway is able to promote SREBP1/SCD1-mediated MUFA formation and convert MUFAs to their acyl-CoA esters under the action of ACSL3 for incorporation into membrane phospholipids, thereby protecting cancer cells from ferroptosis.

Fig. 2. The relationship between AR and ferroptosis.

AR can regulate three metabolic pathways in ferroptosis. On the one hand, AR regulate DECR1 to promote the β-oxidation of PUFA, and regulate the lipid composition in the cell membrane through ACSL3 and ACSL4. On the other hand, AR and its mutant AR-V7 increase oxidative resistance by upregulating the level of GPX4 through GSH metabolism mediated by SLC1A4, SLC1A5 and SLC3A2, respectively. Furthermore, AR can promote STAMP2-mediated redox reactions and increase ferrous iron levels in the cytoplasm. At the same time, iron, GSH, and PUFA can also affect the level of AR through different ways.