Back to Search
Start Over
Targeting of neuroblastoma cells through Kynurenine-AHR pathway inhibition.
- Source :
-
The FEBS journal [FEBS J] 2024 May; Vol. 291 (10), pp. 2172-2190. Date of Electronic Publication: 2024 Mar 03. - Publication Year :
- 2024
-
Abstract
- Neuroblastoma poses significant challenges in clinical management. Despite its relatively low incidence, this malignancy contributes disproportionately to cancer-related childhood mortality. Tailoring treatments based on risk stratification, including MYCN oncogene amplification, remains crucial, yet high-risk cases often confront therapeutic resistance and relapse. Here, we explore the aryl hydrocarbon receptor (AHR), a versatile transcription factor implicated in diverse physiological functions such as xenobiotic response, immune modulation, and cell growth. Despite its varying roles in malignancies, AHR's involvement in neuroblastoma remains elusive. Our study investigates the interplay between AHR and its ligand kynurenine (Kyn) in neuroblastoma cells. Kyn is generated from tryptophan (Trp) by the activity of the enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). We found that neuroblastoma cells displayed sensitivity to the TDO2 inhibitor 680C91, exposing potential vulnerabilities. Furthermore, combining TDO2 inhibition with retinoic acid or irinotecan (two chemotherapeutic agents used to treat neuroblastoma patients) revealed synergistic effects in select cell lines. Importantly, clinical correlation analysis using patient data established a link between elevated expression of Kyn-AHR pathway genes and adverse prognosis, particularly in older children. These findings underscore the significance of the Kyn-AHR pathway in neuroblastoma progression, emphasizing its potential role as a therapeutic target.<br /> (© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Subjects :
- Humans
Cell Line, Tumor
Tryptophan Oxygenase metabolism
Tryptophan Oxygenase genetics
Tryptophan Oxygenase antagonists & inhibitors
Tretinoin pharmacology
Signal Transduction drug effects
Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
Indoleamine-Pyrrole 2,3,-Dioxygenase genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors
Basic Helix-Loop-Helix Transcription Factors genetics
Basic Helix-Loop-Helix Transcription Factors metabolism
Basic Helix-Loop-Helix Transcription Factors antagonists & inhibitors
Cell Proliferation drug effects
Gene Expression Regulation, Neoplastic drug effects
Kynurenine metabolism
Neuroblastoma pathology
Neuroblastoma metabolism
Neuroblastoma genetics
Neuroblastoma drug therapy
Receptors, Aryl Hydrocarbon metabolism
Receptors, Aryl Hydrocarbon genetics
Receptors, Aryl Hydrocarbon antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1742-4658
- Volume :
- 291
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The FEBS journal
- Publication Type :
- Academic Journal
- Accession number :
- 38431776
- Full Text :
- https://doi.org/10.1111/febs.17109