ATF3
Promotes Solasonine‐Triggered Ferroptosis in Glioma Cells by Suppressing Glycolysis
Mingbo Jia, Hexin Xiao, Minghao Shi, Yao Li, Yang Yang, Jianing Zhao, Zhuoyue Shan, Pengfei Ge, Liyan Zhao ABSTRACT
Background
Glioma cells are characterized by rapid proliferation, a high degree of invasiveness, and significant heterogeneity. Despite the application of various treatment regimens in recent years, the prognosis for glioma remains poor. The induction of ferroptosis in tumor cells has emerged as a promising therapeutic approach. Solasonine (SS), a steroidal alkaloid derived from plants of the Solanaceae family, has multiple antitumor effects. However, whether it can inhibit glioma growth and its mechanism of action have not been studied.
Methods
The effects of SS on ferroptosis in glioma cells were analyzed by detecting the levels of ferrous ions, reactive oxygen species, and malondialdehyde. The role of activating transcription factor 3 (ATF3) in SS‐induced ferroptosis in glioma cells was analyzed using western blotting, immunofluorescence, and confocal microscopy. An in vivo mouse model of glioma was constructed to further investigate the effects of SS.
Results
We found that SS inhibited the proliferation of glioma cells and promoted their ferroptosis. SS treatment increased the intracellular ferrous ion, malondialdehyde, and reactive oxygen species levels. It increased the intracellular hydrogen peroxide level by regulating ATF3 to inhibit glycolysis and suppress the antioxidant system. Increased hydrogen peroxide levels activated nuclear receptor coactivator 4–dependent ferritinophagy and increased intracellular iron levels. Furthermore, SS activated the protein kinase RNA–like endoplasmic reticulum kinase/ATF4 endoplasmic reticulum stress pathway by inhibiting glycolysis and promoted ATF3 expression. This process formed a positive feedback loop. In a murine model, SS significantly inhibited glioma cell growth by inducing ferroptosis.
Conclusion
These results indicate that SS promotes glioma cell ferroptosis in vitro and in vivo by inhibiting glycolysis through ATF3.