Farnesol induces apoptosis, LC3B/SQSTM1 mediated regulation of autophagy and downregulates anaerobic Glycolysis through suppression of LDH and PKM in A549 lung adenocarcinoma cells.

Non-small cell lung cancer (NSCLC) is a metabolism associated disease which mainly depends on anaerobic glycolysis to produce the macromolecules needed for biosynthesis and rapid cell proliferation. Since the cancer cells depend on glycolysis for energy production, the development of drug targets that inhibit the glyco-metabolism will be a promising approach for the management of NSCLC. Plant derived phytocompounds have demonstrated anti-NSCLC activity by modulating the glycolytic pathway, thus curbing the energy requirement essential for the proliferation of cancer cells. In the current study, we explored the efficacy of farnesol in A549 lung adenocarcinoma cells using in vitro assays. Farnesol inhibited the viability of A549 cells to 50% at 21.5 µg/mL. Relative proteomic profiling via nano LC-MS/MS analysis identified 277 differentially expressed proteins in control and farnesol treated samples. Notably, PKM (FC = -3.911819), TKT (FC = -2.857373), ALDOA (FC = -4.8557) and LDH (FC = -2.624372) were downregulated exhibiting a strong interacting network in STRING analysis indicating suppression of anaerobic glycolysis. Furthermore, a decrease in the expression of GluIIβ, FBKP1A and apoptotic regulators such as LAP2 and ATP5F subunits suggest initiation of autophagy and apoptosis. AO/EtBr staining confirmed a late apoptotic shift while, DAPI staining revealed nuclear fragmentation at this concentration. Additionally, farnesol impaired mitochondrial ATP synthesis by reducing mitochondrial membrane potential (MMP) to 66% and elevated ROS levels to 54% creating a disturbance in mitochondrial stability. Overall, Farnesol significantly disrupts anaerobic glycolysis in A549 cells promoting cell death through mitochondrial dysfunction, oxidative stress, apoptosis and reducing cellular acidosis.