Eupaformosanin induces apoptosis and ferroptosis through ubiquitination of mutant p53 in triple-negative breast cancer

Abstract

The mutant p53 plays a vital role in the control of cell survival and division under various stresses, including apoptosis and ferroptosis. Here, we showed that eupaformosanin (Eup), a natural compound isolated from Eupatorium cannabinum Linn., significantly inhibited the viability of triple-negative breast cancer (TNBC) cells. Meanwhile, mitochondrial apoptosis contributed to the apoptosis induced by Eup, followed by the disruption of mitochondrial membrane potential (MMP; Δψm) and accumulation of mitochondrial ROS (mt ROS). Apoptosis inhibitor Z-VAD rescued Eup-induced cell death. Afterward, ferroptosis-induced cell death was demonstrated after treatment with Eup, accompanied by lipid reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and iron increase. These events were blocked by ferroptosis inhibitors ferrostatin-1 (Fer-1), deferoxamine (DFO), and liproxstatin-1 (lip-1), indicating that ferroptosis facilitated Eup-induced cell death. Furthermore, Eup regulated mutant p53 ubiquitination. Mutant p53 signaling pathway participated in Eup-induced apoptosis and ferroptosis, which were rescued when mutant p53 was silent in TNBC cells. Also, Eup exerted an anti-TNBC effect by inducing apoptosis and ferroptosis in vivo. Taken together, the data demonstrate that the natural compound Eup is a potential TNBC therapeutic agent that induces apoptosis and ferroptosis through ubiquitination of mutant p53.

Keywords: Apoptosis; Ferroptosis; Mutant p53; Triple-negative breast cancer; eupaformosanin.