Eupaformosanin Induces Apoptosis and Ferroptosis Through Ubiquitination of Mutant P53 in Triple-negative Breast Cancer

Abstract

Purpose Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment. The objective of this study was to find new therapeutic agents and appropriate therapeutic methods and overcome the limitations of TNBC treatment. Methods P53 mutant TNBC cells were treated with eupaformosanin (Eup), a natural compound isolated from Eupatorium cannabinum Linn. Apoptosis and ferroptosis were detected in vitro and in vivo. RNA knockdown was used to investigate the role of mutant p53 in ferroptosis and apoptosis of Eup-induced cell death. A xenograft TNBC animal model was established to assess the anti-TNBC activity of Eup. Results MTT assay suggested that Eup strongly inhibited the viability of TNBC cells. Meanwhile, mitochondrial apoptosis contributed to the cell death in TNBC cells while mitochondrial membrane potential (MMP; Δψm) was disrupted, mitochondrial ROS (mt ROS) was enhanced, and related level of proteins was regulated. Apoptosis inhibitor Z-VAD rescued Eup-induced cell death. Afterwards, ferroptosis-induced cell death was demonstrated in TNBC cells, accompanied by lipid ROS accumulation, GSH depletion and iron increase. These events were blocked by ferroptosis inhibitors Fer-1 and DFO, indicating that ferroptosis facilitated Eup-induced cell death. Furthermore, Eup regulated mutant p53 ubiquitination, and mutant p53 signaling participated in Eup-induced apoptosis and ferroptosis, which were rescued when mutant p53 was silent in TNBC cells. Moreover, Eup exerted an anti-TNBC effect by inducing apoptosis and ferroptosis in vivo.Conclusion The natural compound Eup is a potential TNBC therapeutic agent that induces apoptosis and ferroptosis through ubiquitination of mutant p53.

The potential interplay between G-quadruplex and p53: their roles in regulation of ferroptosis in cancer

“…The complicated models are tightly involved in p53-mediated ferroptosis. Targeting p53 pathways is a promising strategy for anticancer therapy, and various inhibitors are being developed, including ZNF498 (Zhang X. et al, 2022), and Eupaformosanin (Wei et al, 2022).…”