Combined celecoxib and NDGA induces a non-canonical, autophagy-independent redox cell death via p62/KEAP1 in colorectal cancer

A recent study explored the potential of a combination of celecoxib and NDGA (C+N) treatment in inducing cell death in colorectal cancer (CRC) cells, aiming to overcome the challenges posed by genetic diversity and therapeutic resistance. Two CRC cell lines, HCT116 and HT29, with distinct mutations (KRAS and BRAF respectively) and varying p53 status, served as models to investigate the effects of C+N treatment.

The combination treatment displayed significant cytotoxicity, irrespective of COX-2/5-LOX expression and apoptotic competence, indicating a unique mechanism of action. This treatment led to elevated oxidative stress, evidenced by mitochondrial ROS, lipid peroxidation, and an accumulation of labile ferrous iron, which manifested as distinct JC-1 green mitochondrial puncta and FerroOrange red iron puncta in both cell lines.

Intriguingly, while the antioxidant NAC reversed the C+N-induced cell death, inhibitors targeting apoptosis, autophagy, necroptosis, or ferroptosis were ineffective, suggesting a novel mechanism. Mechanistically, C+N treatment resulted in the phosphorylation of p62 Ser349, leading to KEAP1 degradation and NRF2 stabilization, independently of ULK1-mediated autophagy.

However, NRF2 stabilization did not lead to HO-1 induction, highlighting a divergence from the typical redox-related pathways. This research elucidates that C+N treatment induces a redox-mediated cell death mechanism that does not rely on the ULK1/autophagy pathway, thereby bypassing apoptotic competence. The findings underscore the potential of redox disruption as a genotype-independent therapeutic strategy to address the heterogeneity seen in CRC, offering new avenues for targeted cancer therapy.