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

Abstract

BackgroundAs 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).MethodsDifferent 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.ResultsThere 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.ConclusionsLuteolin‐induced ferroptosis in PCa cells by promoting TFEB nuclear translocation and increasing ferritinophagy.

TCM targets ferroptosis: potential treatments for cancer

“…Ferritin autophagy, a process in which ferritin is degraded through autophagy, has been identified as triggering ferroptosis in various cancer cells (Gao et al, 2016;Hou et al, 2016). Luteolin (Fu et al, 2023), Rh4 (Wu et al, 2022) and ursolic acid (Tang et al, 2021a)promote ferroptosis by increasing autophagy. Ferritin is a cytoplasmic iron storage protein, negative feedback protein of Ferroptosis.…”

“…It possesses a wide range of activities, including antioxidant (Ahmadi et al, 2020), anti-inflammatory (Wang et al, 2020a;Gendrisch et al, 2021), antifibrotic (Li et al, 2015), and anticancer properties (Prasher et al, 2022;Matić et al, 2023). Luteolin has been shown to induce ferroptosis in prostate cancer by promoting the nuclear translocation of transcription factor EB (TFEB) and enhancing ferritinophagy (Fu et al, 2023). Heme oxygenase-1 (HMOX1), an inducible enzyme, is considered a measurable indicator of oxidative stress (Maines, 1997).…”

Luteolin targets the AGE-RAGE signaling to mitigate inflammation and ferroptosis in chronic atrophic gastritis

“…Notably, luteolin-mediated ferroptosis has different effects on different cells. Luteolin can induce ferroptosis in cancer cells such as prostate cancer [ 27 ], colorectal cancer [ 28 ], and renal cell carcinoma [ 29 ], while inhibiting ferroptosis in normal cells [ 19 , 30 ]. Ferroptosis is mainly caused by the action of bivalent iron ion or ester oxygenase, which catalyzes the highly expressed unsaturated fatty acids on the cell membrane and causes liposome peroxidation, thus inducing cell death [ 31 ].…”