SNCA Overexpression Induces Apoptosis in Non-Small Cell Lung Cancer via Caspase-Dependent Signaling Pathways

The alpha-synuclein (SNCA) gene is a Parkinson's disease (PD)-associated gene that is found to be downregulated in non-small cell lung cancer (NSCLC). Aberrant SNCA expression exerts neurotoxicity in PD by disrupting mitochondrial function, promoting protein aggregation or oxidative stress, ultimately leading to neuronal cell death. Numerous studies have hypothesized that SNCA is a tumor suppressor gene, but the underlying mechanism remains elusive. In this study, the SNCA gene is delivered to NSCLC cells via transfection of a plasmid vector with carbonate apatite (CA) nanoparticles as the delivery vehicle. Biochemical assays including cytotoxicity assay, oxidative stress assay, flow cytometry, and caspase activity assay were performed to assess the effects of SNCA overexpression in NSCLC cells. SNCA-overexpressed NSCLC cells were established using the optimized CA/plasmid complexes. SNCA overexpression promoted oxidative stress-induced cell death and apoptosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cells. Additionally, SNCA overexpression activated distinct caspases' activities in LUAD and LUSC. Besides, this study reveals that LUSC was more susceptible to the anticancer effects of SNCA overexpression than LUAD. As a result, SNCA overexpression promoted apoptosis under oxidative stress in NSCLC cells via distinct caspases' activations.