Grain Alcohol Extracts Inhibit Tumor Cell Proliferation By Promoting Lipid De Novo Synthesis

Natural products are valuable resources for screening anti-tumor drugs and serve as critical complements to chemically synthesized drugs.Plants contain thousands of metabolites that possess efficacious properties for treating diseases.Foxtail millet(Setaria Italica),a plant belonging to the grass family,is commonly referred to as millet after undergoing peeling.Millet holds a significant position in Shanxi’s miscellaneous grain resources,and promoting the millet industry is advantageous for Shanxi’s characteristic economic development.Millet is a typical crop that has been consumed as both food and medicine for years because of its rich nutritional content.Modern research has discovered that millet has an abundance of bioactive compounds,and among them,the most intriguing research area is anti-tumor activity.The energetic metabolism of lipid synthesis in tumor cells is vigorous.Further promotion of lipid synthesis can induce the already delicate oxidative-reductive steady state of the tumor cells to collapse,ultimately resulting in cell death.This new direction towards developing anti-tumor drugs involves discovering a natural activator from millet that could induce de novo synthesis of lipids in tumor cells.Our study,using a fat cell differentiation model,found that 70% ethanol elution fraction(MWGAE70)extracted from millet significantly promotes de novo synthesis of cell lipids and remains stable across different drug batches.Based on the association between lipid metabolism,cancer development,and the TCGA database,we conducted this study using a breast cancer model.Our analysis indicated that MWGAE70 have an excellent anti-tumor efficacy both in vitro and in vivo,and explored its anti-tumor mechanism.Our results indicated that it was closely associated with de novo synthesis of lipids.Our experimental results reveal that under MWGAE70’s influence,the oxidative-reductive steady state of breast cancer cells affected,causing reactive oxygen species to spike,an increase in glucose uptake rate,and decreased energy production.Increasing drug concentrations steadily heightened active oxygen in cells.Furthermore,gene expression of PTGS2 and ACSL4,which strongly correlate with ferroptosis increased,suggesting that after drug treatment the risk of ferroptosis in tumor cells escalated.After verifying MWGAE70’s potential to reduce breast cancer cell proliferation through several metabolic reprogramming methods,we identified four components via mass spectrometry.The results demonstrated that flavonoids amounted to a minuscule proportion in MWGAE70,and the relatively high concentration of pine aldehyde was not a key component.We identified key molecules by conducting cell experiments and using mass spectrometry to explore the dose-response relationship between different components of the same batch of compounds.Our study illustrates that the promotion of de novo synthesis of cell lipids,leading to a heightened level of active oxygen in tumor cells,decreased production of cell energy,and an increased risk of ferroptosis,is the core mechanism by which MWGAE70 exhibits excellent anti-breast cancer effects.This discovery offers a new approach to treating tumors and the potential for high-value development in the millet industry.