Ferroptosis and its Role in Gastric Cancer

Abstract

Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Currently, surgery is the treatment of choice for GC. However, the associated expenses and post-surgical pain impose a huge burden on these patients. Furthermore, disease recurrence is also very common in GC patients, thus necessitating the discovery and development of other potential treatment options. A growing body of knowledge about ferroptosis in different cancer types provides a new perspective in cancer therapeutics. Ferroptosis is an iron-dependent form of cell death. It is characterized by intracellular lipid peroxide accumulation and redox imbalance. In this review, we summarized the current findings of ferroptosis regulation in GC. We also tackled on the action of different potential drugs and genes in inducing ferroptosis for treating GC and solving drug resistance. Furthermore, we also explored the relationship between ferroptosis and the tumor microenvironment in GC. Finally, we discussed areas for future studies on the role of ferroptosis in GC to accelerate the clinical utility of ferroptosis induction as a treatment strategy for GC.

Keywords: ROS; drug resistance; ferroptosis; gastric cancer; iron; microenvironment.

FIGURE 1

Mechanisms of ferroptosis. Excess iron is related to lipid peroxidation and abnormal iron metabolism of mercaptan, which induces the production of ROS. On the one hand, circulating iron in the form of Fe³⁺ binds to the transferrin receptor and enters the cell. Iron oxide reductase, STEAP3, reduces Fe³⁺ to Fe^{2 +}, which is transported to the iron pool through DMT1 to induce the formation of ROS. Finally, it promotes lipid peroxidation and causes ferroptosis. On the other hand, the Xc system transports intracellular Glu to the extracellular space and extracellular cystine simultaneously into the cells, which is then transformed into cysteine for GSH synthesis. GPX4 converts -OOH to -OH in polyunsaturated fatty acid (PUFA) to reduce ROS accumulation.

FIGURE 2

Contribution of iron and macrophages in the tumor microenvironment of gastric cancer. Macrophages maintain iron balance in human tissues. The proliferation of GC cells requires a large amount of iron, and the increased iron flow from tumor-associated macrophages promotes tumor progression or tumor protraction.

FIGURE 3

Drug resistance and ferroptosis in gastric cancer. (A) Exosomal mir-522 secreted from cancer-associated fibroblasts (CAFs) enter the GC cells and bind to ALOX15 mRNA, resulting in ALOX15 inhibition and reduction in lipid-ROS accumulation in cancer cells. It inhibits ferroptosis in GC cells, and finally reduces chemosensitivity (Namee and O'Driscoll, 2018). (B) Exosomal lnc-ENDOG-1:1 from GC cells can promote the expression of SCD1 by directly interacting with the SCD1 mRNA in GC cells and recruiting heterogenous ribonucleoprotein A1 (hnRNPA1), thereby leading to the inhibition of ferroptosis in GC cells.