System Xc -/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

Abstract

The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System X_c ^-), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System X_c ^-/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System X_c ^-/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System X_c ^-/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.

Keywords: drug resistance; ferroptosis; solid tumor; system Xc -/GSH/GPX4 axis; therapy.

FIGURE 1

The regulation pathway of System Xc⁻/GSH/GPx4 in ferroptosis. ① System Xc⁻ transport cystine into the cell and reverse Glu out of the cell in a 1:1 ratio. ② Cystine absorbed by System Xc⁻ is reduced to cysteine by G-SH or TrxR1. ③ Then GCL links cysteine and glutamate to produce γ-GC. ④ γ-GC and Gly are catalyzed by GSS to produce G-SH. ⑤In the catalytic cycle of GPx4, the GPx4-SeH is oxidized by the P-LOOH to GPx4-SeOH, while G-SH can reduce -SeOH and further activates GPx4, releasing GS-SG to prevent GPx4 from being inactivated. ⑥GS-SG is reduced to G-SH under the action of GR and Coenzyme NADPH. Since P-LOOH is reduced to PLOH by GPx4-SeH, ferroptosis is inhibited. ⑦Fe²⁺ can produce a large number of PLOOH through the Fenton reaction.

FIGURE 2

The potencial roles of System Xc-/GSH/GPx4 in drug-resistant solid tumor. ① SLC7A11, highly expressed in NSCLC, is a potential target for ferroptosis. SLC7A11 downregulation lead to ferroptosis of lung cancer cells and inhibit their growth. In addition to SLC7A11, lung cancer cell also exhibits high GPx4 expression. GPX4 inhibitor limits proliferation, migration, and invasion of cisplatin-resistant lung cancer cells. ② Drug-resistant breast cancer cells are dependent on GPX4 and SLC7A11. SLC7A11 is upregulated in one-third of TNBC cells in vivo, and inhibiting System Xc-activity increases intracellular ROS levels and slows TNBC metabolism. Inhibition of GPX4 and/or System Xc-may be a potential measure to overcome drug resistance in breast cancer. ③ The main regulatory mediators mediating the ferroptotic response in HCC cells have been identified as System Xc-and GPX4. blocking System Xc -/GSH/GPX4 axis in combination with chemotherapeutic agents (e.g., sorafenib) provides new ideas for treatment of drug-resistant HCC. ④ GPx4 is lowly expressed in GC cells, making them more susceptible to ferroptosis than normal intestinal cells. Reducing the expression of GPX4 and System Xc-inhibiting the proliferation of GC cells and multidrug-resistant GC. ⑤ In CSCs, SLC7A11 is extremely expressed, with high GSH levels and low ROS levels, leading to their extreme vulnerability to ferroptosis. Similar to GC cells, targeting the System Xc-/GSH/GPX4 axis is an effective way to inhibit the growth of drug-resistant colorectal cancer. ⑥ LONP1 inhibits Nrf2-mediated GPX4 gene expression, thereby promoting Erastin-induced ferroptosis in human PDAC cells. The use of System Xc-inhibitors enhanced the cytotoxic effect of gemcitabine and cisplatin on PDAC cell lines. Gemcitabine resistance was associated with GPx4 upregulation in PDAC cells. Inhibition of GPX4 activity or induction of GPX4 degradation can restore or enhance the anticancer activity of gemcitabine in vitro or in xenogeneic PDAC models.