Activation Ferroptosis Enhanced the Therapy Sensitivity of TNBC to Paclitaxel Via NCOA4 Mediated Ferritinophagy

Abstract BackgroundPaclitaxel (PTX) is the first-line drug for chemotherapy, but Triple-Negative Breast Cancer (TNBC) develops resistance to PTX is the main challenge in clinical therapy. Ferroptosis is a new type of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation accumulation, despite activation of ferroptosis has been shown to enhance the sensibility of tumor to chemotherapy drugs, the underlying mechanism remains unclear. MethodsC11-BODIPY probe and real time PCR was used to detect the ferroptosis level in breast cancer cells. FerroOrange probe and western blot was employed to measure ferritinophagy. The cell viability was examined by CCK-8, EdU and AM/PI double staining.ResultsThe anti-cancer effect of PTX was related to the induction of ferroptosis in TNBC cells, the ferroptosis occurring was mediated by NCOA4-driven ferritinophagy, and the autophagy-related molecules also downregulated in clinical specimens. Furtherly, TNBC cells survival was decreased more significantly than PTX alone when combining with ferroptosis agonist RSL3. In addition, we also discovered that HERC2, a unique identified E3 ubiquitin ligase of NCOA4, obviously expressed downregulation under PTX treated TNBC cells while elevated in breast carcinoma comparing with adjacent tissues. Meanwhile, bioinformatics results showed that the survival rate was significantly lower in breast cancer patients with high expression of HERC2.ConclusionsFerroptosis agonist can assist PTX to enhance the sensitivity of TNBC to PTX in chemotherapy, which possible mechanism is prompting the expression of NCOA4 and the occurrence of ferritinophagy.