Blockage of BAG2-CHIP Axis Combats Gastric Cancer by Inducing HSP70 Ubiquitination-mediated Apoptosis

Abstract The acquired resistance of cells to apoptosis is strongly correlated with the development of gastric cancer. Bcl-2-associated athanogene 2 (BAG2) functions as an oncogene in numerous tumours by regulating cell apoptosis. However, its functional, clinical importance and underlying mechanism in gastric cancer (GC) remain unclear. Here, we reported BAG2 as a therapeutic target to regulate GC apoptosis through BAG2-CHIP-HSP70-Apaf1-Cytc axis. BAG2 is highly overexpressed in GC and negatively correlated with prognosis of patients with GC. Knockout of BAG2 inhibits GC growth and induces cell apoptosis in vitro and in vivo. Mechanistically, BAG2 interacts with C-terminus of HSP70-inteacting protein (CHIP) to inhibit the ubiquitination degradation of HSP70, resulting in an increase in the binding of HSP70 and Apoptotic protease activating factor (Apaf1), and in turn reduction of mitochondrial Cytochrome C (Cytc) release to block cell apoptosis. In addition, we identified FIIN-2 as an inhibitor of the BAG2-CHIP complex, which induces apoptosis to inhibit GC growth in GC cell lines, organoids and CDX mice models. In conclusion, we characterize that BAG2 drive the GC growth by regulating cell apoptosis through BAG2-CHIP-HSP70-Apaf1-Cytc axis, and blockage of BAG2-CHIP using FIIN-2 as a potential strategy to combat GC.