Oncogenic Mutant p53 Sensitizes Non–Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress–Dependent Induction of Mitochondrial Apoptosis

摘要: Non–small cell lung cancer (NSCLC) cells with oncogenic mutant p53 (Onc-p53) alleles exhibit significantly higher levels of proteasome activity, indicating that Onc-p53 induces proteotoxic stress which may be leveraged as a therapeutic vulnerability. Proteasome inhibitors (PI) are most active in cells under proteotoxic stress, so we investigated whether PIs exhibit preferential cytotoxicity in Onc-p53 NSCLC cells. Indeed, bortezomib (BTZ) and other PIs exhibited IC50 values 6- to 15-fold lower in Onc-p53 cells versus wild-type (WT) p53 cells. BTZ cytotoxic effects in Onc-p53 cells were abrogated by antioxidants such as N-acetyl-L-cysteine, indicating that oxidative stress is the critical driver of BTZ-dependent cytotoxic effects in Onc-p53 cells. Importantly, we observed oxidative stress–dependent transcriptional induction of the proapoptotic BH3-only protein NOXA, leading to cleavage of caspase-3, consistent with …