This study aimed to investigate the effects and underlying mechanisms of V9302, an inhibitor of glutamine transport, on non-small cell lung cancer (NSCLC) cells. Proliferation was assessed using the cell counting kit-8, colony formation, and EdU assays. Mitochondrial membrane potential was evaluated through JC-1 staining. Cell cycle distribution, apoptosis, and reactive oxygen species (ROS) levels were analyzed by flow cytometry, while migration was assessed using wound healing and Transwell assays. Western blotting was performed to determine protein expression levels. The antitumor efficacy of V9302 in vivo was evaluated using a xenograft mouse model with PC-9 cells. The results demonstrated that V9302 inhibited cell proliferation and induced G1-phase arrest in human lung adenocarcinoma PC-9 and A549 cells. Western blotting showed that V9302 significantly inhibited the ASCT2 protein expression in both PC-9 and A549 cells. Additionally, V9302 promoted apoptosis through a mitochondrial-dependent pathway, as evidenced by elevated levels of cleaved PARP, cleaved Caspase 3, cleaved Caspase 9, and Bax. V9302 also suppressed cell migration by downregulating N-cadherin and vimentin expression. Notably, V9302 triggered significant ROS accumulation and inhibited mTOR/p70S6K pathway activation, an effect that was partially restored by N-acetylcysteine, a ROS scavenger. Pretreatment with mTOR activator MHY1485 mitigated the inhibitory effects of V9302 on cell proliferation and migration, as well as its induction of apoptosis. Furthermore, V9302 inhibited tumor growth and induced apoptosis in a xenograft mouse model, without inducing detectable visceral toxicity. In conclusion, these findings demonstrate that V9302 reduces cell proliferation and migration, and causes apoptosis through the ROS-mediated mTOR/p70S6K pathway in NSCLC cells. These findings provide a novel theoretical foundation for advancing both academic and clinical research on NSCLC treatment.
Li et al. (Thu,) studied this question.