β-Elemene Inhibits Proliferation of Non-Small-Cell Lung Cancer by Targeting ALDH3A1 to Regulate Metabolic Reprogramming

Background Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in the world. Although the improvement of treatment has significantly prolonged the survival of NSCLC patients, most patients still face recurrence because of drug resistance. Therefore, it is urgent to find more effective drugs to improve the NSCLC treatment and survival rate of patients. Methods Network pharmacology tools were comprehensive applied to analyze β-elemene and the anticancer effects of β-elemene were evaluated both in vitro and in vivo. What’s more, the underlying mechanisms were investigated via metabolomics analysis, 18FDG-micro-PET scan and molecular biology experiment. Results β-elemene exhibited potent inhibitory effects on NSCLC cells proliferation by alternating the cell cycle without significantly apoptosis in NSCLC cells. Mechanistically, we found that β-elemene regulating metabolic reprogramming of NSCLC via targeting Aldehyde Dehydrogenase 3 Family Member A1 (ALDH3A1). Subsequently, the metabolic reprogramming of NSCLC cells regulated by β-elemene lead to increased hydroxylation of α-ketoglutarate (α-KG), and degraded Hypoxia Inducible Factor1 Subunit Alpha (HIF1α), which cause accelerated reduction of aerobic glycolysis in NSCLC in vivo and vitro through facilitating HIF1α/LDHA pathway. Moreover, the reduction of aerobic glycolysis effect of β-elemene in vivo was confirmed by the reduced SUV values and the decreased expression of Ki-67 and HIF1α/LDHA pathway proteins in tumor tissues from xenograft mouse models. Conclusion β-Elemene exhibits strong metabolic reprogramming effects, glycolysis was suppressed while OXPHOS was increased in NSCLC cells via targeting ALDH3A1 and HIF1α/LDHA pathway, which provides a new theoretical basis for the clinical treatment of patients with NSCLC.