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Erdafitinib promotes ferroptosis in human uveal melanoma by inducing ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling axis.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2024 Sep; Vol. 222, pp. 552-568. Date of Electronic Publication: 2024 Jul 05. - Publication Year :
- 2024
-
Abstract
- Uveal melanoma (UM) is a rare yet lethal primary intraocular malignancy affecting adults. Analysis of data from The Cancer Genome Atlas (TCGA) database revealed that FGFR1 expression was increased in UM tumor tissues and was linked to aggressive behavior and a poor prognosis. This study assessed the anti-tumor effects of Erdafitinib, a selective pan-FGFR inhibitor, in both in vitro and in vivo UM models. Erdafitinib exhibited a robust anti-cancer activity in UM through inducing ferroptosis in the FGFR1-dependent manner. Transcriptomic data revealed that Erdafitinib mediated its anti-cancer effects via modulating the ferritinophagy/lysosome biogenesis. Subsequent research revealed that Erdafitinib exerted its effects by reducing the expression of FGFR1 and inhibiting the activity of mTORC1 in UM cells. Concurrently, it enhanced the dephosphorylation, nuclear translocation, and transcriptional activity of TFEB. The aggregation of TFEB in nucleus triggered FTH1-dependent ferritinophagy, leading to lysosomal activation and iron overload. Conversely, the overexpression of FGFR1 served to mitigate the effects of Erdafitinib on ferritinophagy, lysosome biogenesis, and the activation of the mTORC1/TFEB signaling pathway. In vivo experiments have convincingly shown that Erdafitinib markedly curtails tumor growth in an UM xenograft mouse model, an effect that is closely correlated with a decrease in FGFR1 expression levels. The present study is the first to demonstrate that Erdafitinib powerfully induces ferroptosis in UM by orchestrating the ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling. Consequently, Erdafitinib emerges as a strong candidate for clinical trial investigation, and FGFR1 emerges as a novel and promising therapeutic target in the treatment of UM.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Pyrazoles pharmacology
Cell Line, Tumor
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic drug effects
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics
Cell Proliferation drug effects
Mice, Nude
Receptor, Fibroblast Growth Factor, Type 1 metabolism
Receptor, Fibroblast Growth Factor, Type 1 genetics
Mechanistic Target of Rapamycin Complex 1 metabolism
Mechanistic Target of Rapamycin Complex 1 genetics
Lysosomes metabolism
Lysosomes drug effects
Ferroptosis drug effects
Ferroptosis genetics
Melanoma drug therapy
Melanoma metabolism
Melanoma pathology
Melanoma genetics
Signal Transduction drug effects
Quinoxalines pharmacology
Uveal Neoplasms drug therapy
Uveal Neoplasms metabolism
Uveal Neoplasms pathology
Uveal Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 222
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38971541
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2024.07.002