Luteolin induces ferroptosis in prostate cancer cells by promoting TFEB nuclear translocation and increasing ferritinophagy

Abstract Background As the second most common cancer in men and the leading cause of cancer‐related death, prostate cancer (PCa) could potentially be treated by inducing ferroptosis. In this study, we aimed to investigate whether luteolin could induce ferroptosis in PCa cells through the transcription Factor EB (TFEB). Methods Different concentrations of luteolin were applied to treat normal prostate epithelial cells RWPE‐1 and PCa cell lines DU145, PC‐3, VCaP, and LNcaP. Ferrostatin‐1 (Fer‐1), Necrostain‐1 (Nec‐1), 3‐methyladenine (3‐MA), chloroquine (CQ), and the apoptosis inhibitor benzyloxycarbonyl‐Val‐Ala‐Asp(OMe)‐fluoromethylketone (Z‐VAD‐FMK) were added to treat DU145 and PC‐3 cells. Additionally, we knocked down TFEB and performed in vitro cell experiments. Finally, tumor‐forming experiments in nude mice were conducted to verify luteolin mechanism in PCa after knocking down TFEB. Results There was no significant difference in RWPE‐1 at 12, 24, and 48 h after treatment with 60 μM luteolin. However, a significant difference was observed between DU145 and PC‐3 cells. Luteolin exhibited a promoting effect on PCa cell death. After treatment with luteolin, cell viability, and Ki67 expression were decreased, and AnV‐PI‐positive dead cells were increased. Fer‐1, Nec‐1, 3‐MA, and Z‐VAD‐FMK reversed luteolin effects on DU145 and PC‐3 cell viability, proliferation, and AnV‐PI‐positive dead cells. Among them, Fer‐1 and 3‐MA were more effective. Luteolin‐induced increased autophagy and ferroptosis in DU145 and PC‐3 cells. Moreover, luteolin promoted ferroptosis by inducing increased autophagy in DU145 and PC‐3 cells. However, knockdown of TFEB reversed the ability of luteolin to induce lysosome degradation of ferritin. In addition, luteolin promoted PCa ferroptosis by inducing ferritinophagy in vivo. Conclusions Luteolin‐induced ferroptosis in PCa cells by promoting TFEB nuclear translocation and increasing ferritinophagy.