MDM2 inhibition by nutlin-3 shift pyroptosis to apoptosis in lung carcinoma cells undergoing 5-FU treatment

Aim To investigate what cell death mode is dominat in non-small cell lung cancer (NSCLC) tissue and cell line, and the role played byMDM2-p53 pathway in the transition of pyroptosis to apoptosis during chemotherapy Materials and Methods Patients with NSCLC were consecutively recruited in Gansu Provincial Hospital from December 2016 to January 2018. The protein expressions of GSDMD, GSDME, and MDM2 were compared between cancer and adjacent tissues in NSCLC patients, as well as between normal human respiratory epithelium HBE cells and A549 carcinoma cells. A549 and HBE cells were treated with Nutlin-3 to inhibit the MDM2 function in the presence of 5-Fluorouracil (5-FU). Results Both GSDMD and GSDME were expressed in NSCLC tissues, while only GSDME was expressed in A549 and HBE cells. The execution effective N-terminal of GSDME, but not of GSDMD was expressed in NSCLC tissue, and A549 and HBE cells after chemotherapeutic drug treatments. GSDME overexpression in both A549 and HBE cells increased pyroptosis. The expression of MDM2 measured by IHC was significantly higher in cancer tissues. Nutlin-3, a specific inhibitor of MDM2 binding to P53, significantly decreased the total cell survival rate and pyroptosis, but increased apoptosis in A549 cells treated with 5-FU. Nutlin-3 did not show any effect on HBE cells. Conclusions GSDME expression in the lung carcinoma determines pyroptosis sensitivity and the occurrence of severe side effects. MDM2 inhibition shifts pyroptosis to apoptosis, which may be useful in increasing the anti-tumor effects and preventing pyroptosis-induced side effects in lung cancer chemotherapy.