Sanggenon C induces P53-mediated apoptotic cell death associated with modulation of the MDM2-P53 axis in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality and is characterized by disruption of P53-dependent cell death pathways. The present study investigated the effects of sanggenon C (SC), a natural polyphenolic compound, on cell death regulation focusing on the murine double minute 2 (MDM2)-P53 axis. SC was evaluated in NSCLC cell lines with different TP53 statuses and in xenograft and lung colonization models. SC preferentially induced apoptotic cell death in TP53 wild-type cells compared with TP53-mutant or TP53-null cells, accompanied by reduced clonogenic survival, migration, and invasion in P53-proficient cells, as well as decreased tumor burden and lung colonization in vivo in a TP53-dependent manner. Mechanistically, SC enhanced P53 protein stability by reducing ubiquitination and prolonging its half-life without altering TP53 mRNA expression, as demonstrated by cycloheximide chase and ubiquitination assays. DARTS-LC-MS/MS identified 72 candidate SC-associated proteins, and subsequent biochemical validation, including microscale thermophoresis and co-immunoprecipitation, implicated MDM2 as an SC-associated binding partner, further supported by molecular docking and molecular dynamics analyses. Consistently, SC decreased MDM2 protein abundance, while MDM2 overexpression partially attenuated SC-induced P53 stabilization. These findings indicate that SC induces P53-mediated apoptotic cell death in association with modulation of the MDM2-P53 axis.