Apatinib inhibits gastric cancer progression by inducing ferroptosis through cysteine dioxygenase 1/phosphoinositide 3-kinase/Akt axis.

Although the clinical efficacy of apatinib in advanced gastric cancer has been widely confirmed, its anticancer mechanism still needs to be further studied. This study found that apatinib significantly inhibited gastric cancer cell viability by inducing the expression of cysteine dioxygenase 1 (CDO1; a key ferroptosis regulatory gene) and then enhancing ferroptosis, and CDO1 knockdown reduced ferroptosis. Apatinib and CDO1 significantly downregulated the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, reduced cell viability and glutathione production, promoted acyl-CoA synthetase long chain family member 4 expression, and increased the accumulation of reactive oxygen species, Fe2+, and malondialdehyde; when knocking down CDO1 expression or activating phosphoinositide 3-kinase (PI3K)/Akt pathway, the expression of key ferroptosis regulatory genes and the contents of ferroptosis markers were significantly restored, indicating that apatinib-induced ferroptosis is associated with CDO1/PI3K/Akt axis. Meanwhile, both apatinib and CDO1 significantly inhibited the expression and secretion of metalloproteinase (MMP)-2 and MMP-9, and reduced cell invasion and migration; the ferroptosis inhibitor Fer-1, CDO1 small interfering RNA, and PI3K/Akt pathway activator 740 Y-P all weakened the regulation of apatinib and CDO1 on MMP expression, cell invasion and migration. Further in vivo nude mouse tumorigenesis experiments showed that apatinib significantly inhibited tumor growth and the expression of glutathione peroxidase 4 and solute carrier family 7 member 11, promoted CDO1 and acyl-CoA synthetase long chain family member 4 expression, increased reactive oxygen species, Fe2+, and malondialdehyde contents, and reduced glutathione production; after knocking down CDO1 expression, all these ferroptosis indicators were significantly restored. Therefore, apatinib inactivates PI3K/Akt pathway by promoting CDO1 expression, thereby enhancing ferroptosis and then inhibiting tumor growth. SIGNIFICANCE STATEMENT: Apatinib is a small-molecule tyrosine kinase inhibitor and can inhibit tumor cell growth through various mechanisms other than antiangiogenesis. Therefore, understanding the anticancer mechanism of apatinib is of great significance for its clinical application.