Rabeprazole inhibits lung cancer progression by triggering NLRP3/CASP-1/caspase-dependent pyroptosis.

BACKGROUND

Gastric acid-related diseases could be treated using proton pump inhibitors (PPIs), which have been found to have anti-tumor ability. Rabeprazole is a type of PPI whose effect and mechanism in lung cancer remained to be clarified.

METHODS

Lung cancer cells and lung cancer mice were treated with different concentrations of Rabeprazole and then cell proliferation was detected by CCK-8 and colony formation assays. Pyroptosis was assessed by morphological observation and Lactate dehydrogenase (LDH) release assays. Western blot, immunofluorescence and immunohistochemistry were adopted to detect the expressions of GSDMD and NLRP3. Reactive oxygen species (ROS) level, lysosomal damage and autophagic flux were measured by flow cytometry.

RESULTS

Rabeprazole suppressed lung cancer cell proliferation and lung tumor growth in mice in a concentration-dependent manner. Lung cancer cells treated with Rabeprazole showed typical pyroptosis morphology and significantly increased LDH release. Rabeprazole upregulated the expression of GSDMD, NLRP3, and cleaved-Caspase 1, but such an effect was partially blocked by Z-LLSD-FMK. In lung cancer cells treated with Rabeprazole and lung cancer mice injected with Rabeprazole, the expressions of GSDMD, NLRP3 and caspase-1 were promoted, ROS-stained cells were increased significantly, lysosomal damage was aggravated, and autophagic flux was noticeably reduced.

CONCLUSIONS

Rabeprazole activated NLRP3/caspase 1/GSDMD cascade by promoting ROS accumulation and lysosomal destruction, thereby inducing pyroptosis to fulfill its anti-tumor effect on lung cancer.