Arsenic-Induced PPARγ, with the Coordinated Action of p62, Inhibits Apoptosis and Necroptosis and Activates the DNA Damage Response in A549 Lung Cancer Cells, Leading to Carcinogenesis

Arsenic exposure increases lung cancer risk, yet its molecular mechanisms remain unclear but are linked to peroxisome proliferator-activated receptor gamma (PPARγ). We investigated PPARγ-related molecules affected by sodium arsenite (NaAR) in non-small cell lung cancer (NSCLC) cells using immunochemical, gene knockdown, and immunoprecipitation approaches. PPARγ was critical for NSCLC growth, as high PPARγ-expressing A549 cells proliferated more than low-expressing H1299 cells after NaAR treatment. In A549 cells, NaAR upregulated polyubiquitinated PPARγ, activating cell cycle arrest and DNA damage response pathways. Rather than inducing significant caspase-dependent apoptosis, NaAR activated nuclear factor-kappa B and downregulated mixed lineage kinase domain-like (MLKL) via K63-linked polyubiquitinated receptor-interacting protein kinase 1, thereby inhibiting apoptosis and necroptosis. PPARγ knockdown or NAD+ supplementation induced PARP-1 hyperactivation and MLKL upregulation, leading to DNA damage and necroptosis. PARP-1 inhibition by 3-aminobenzamide induced apoptosis, indicating that PPARγ regulates apoptosis and necroptosis through PARP-1 activation. Proteasome inhibition increased polyubiquitinated PPARγ but not p53. Leptomycin B induced PPARγ degradation and p53 accumulation, promoting necroptosis and apoptosis, suggesting cytoplasmic p53 contributes to cell death. p62 interacted with PPARγ and p53, and its knockdown suppressed their NaAR-induced upregulation. In conclusion, NaAR-induced PPARγ promotes A549 cell survival by enhancing DNA repair and inhibiting apoptosis and necroptosis via cooperation with p53 and p62, highlighting PPARγ as a potential therapeutic target.