Arenobufagin Induces Ferroptosis in Glioblastoma Cells via Modulating the MiR-149-5p/AEBP1 Axis.

Abstract

Accumulating evidences have proved Arenobufagin (ArBu) exhibited cytotoxic effects to multiple types of cancer. However, in glwioblastoma (GBM), which is easy to develop resistance to classic chemotherapy reagent, the therapeutic effects of ArBu have not been explored. In the current study, we found that GBM cells were sensitive to ArBu treatment and ArBu induced cell death both in a dose-dependent and a time-dependent manner. ArBu was observed to promote ROS accumulating and elevate Fe²⁺/MDA/GSH level, which lead to ferroptosis. Mechanistically, ArBu significantly downregulated AEBP1 expression and decreased the mRNA stability of AEBP1 without affecting its transcription. Then, AEBP1 mRNA was predicted to bind with miR-149-5p in GBM cells, which directly target its 3'UTR. At last, we found ArBu could upregulate miR-149-5p to suppress AEBP1 expression, and the rescue experiments confirmed miR-149-5p/AEBP1 axis regulated ferroptosis, which underlay the therapeutic effects of ArBu in GBM cells. This study revealed that ArBu induced ferroptosis in a dose-dependent manner via modulating miR-149-5p/AEBP1 axis. It provides evidences for clinical application of ArBu for GBM.