학술논문
Targeting of neuroblastoma cells through Kynurenine-AHR pathway inhibition.
Document Type
Academic Journal
Author
Dos Santos IL; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Mitchell M; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pediatrics, University of Texas Dell Medical School, Austin, TX, USA.; Nogueira PAS; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Lafita-Navarro MC; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Perez-Castro L; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Eriom J; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Kilgore JA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Williams NS; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Guo L; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Xu L; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Conacci-Sorrell M; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Source
Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE
Subject
Language
English
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.
(© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
(© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)