Simeprevir induces ferroptosis through β-TrCP/Nrf2/GPX4 axis in triple-negative breast cancer cells.

Abstract

The effective treatment regimens of triple-negative breast cancer (TNBC), a specific subtype of breast cancer (BC) with proneness to relapse and poor prognosis, are still lacking. Simeprevir (SIM), approved for hepatitis C infection treatment, has been proved to be a competitive drug for the treatment of various solid tumors recently. However, the anti-tumor mechanisms of SIM and therapeutic effects on TNBC are uncertain. In this study, we suggested that SIM effectively restrained the growth of MDA-MB-231 and BT-549 cells, two cell lines from TNBC. The RNA sequencing revealed that ferroptosis signaling was activated in SIM-treated TNBC cells. SIM induced ferroptosis in TNBC cells through reduced glutathione (GSH) levels, increased iron levels, ROS and lipid peroxidation. Mechanistically, SIM promoted the expression of β-TrCP to inhibit the Nrf2/GPX4 axis in TNBC cells, leading to ferroptosis. Moreover, SIM administration into the xenografts formed by MDA-MB-231 dramatically suppressed the tumor progression by inducing ferroptosis in vivo. Collectively, this finding reveals that SIM may serve as a competitive therapeutic strategy to inhibit TNBC.