Casticin inhibits proliferation of Non-small cell lung cancer cells through regulating reprogramming of glucose metabolism.

Abstract

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with poor prognosis due to its rapid progression and resistance to existing therapies. Metabolic reprogramming, particularly alterations in glucose metabolism, is a key mechanism underlying tumor growth and progression, providing potential targets for novel therapeutic strategies. Casticin (CAS), a bioactive flavonoid, has shown anticancer effects in various cancers, but its specific role in NSCLC metabolism remains unclear.

Purpose: This study aims to investigate the effects of casticin on the proliferation and glucose metabolism of NSCLC cells, and to explore its underlying mechanisms.

Study design and methods: We used both in vitro and in vivo models. (18)F-FDG PET/MR imaging was employed to assess the impact of casticin on glucose metabolism in A549 xenograft mice. NSCLC cell lines (A549 and H157) were treated with casticin to evaluate its effects on cell viability, glycolysis, oxidative phosphorylation, and fatty acid oxidation. Key metabolic enzyme expressions were analyzed using molecular detection techniques, and in vivo validation was performed using a subcutaneous xenograft mouse model.

Results: Casticin significantly inhibited glucose metabolism and cell proliferation in a dose-dependent manner, while promoting oxidative phosphorylation without affecting lipid metabolism. The drug suppressed glycolysis by downregulating the expression of key glycolytic enzymes (GLUT1, HK2, GPI, ALDOA, ENO2, PKM2, and MCT4) through the regulation of HIF-1α. Overexpression of HIF-1α in both in vitro and in vivo models reversed the inhibitory effects of casticin, indicating that HIF-1α plays a central role in its mechanism of action.

Conclusion: Casticin inhibits NSCLC cell proliferation by suppressing glycolytic reprogramming via HIF-1α regulation. These findings highlight the potential of casticin as an anticancer therapeutic, particularly in targeting glucose metabolism in NSCLC.