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Targeting of neuroblastoma cells through Kynurenine-AHR pathway inhibition.
Dos Santos, Igor Lopes; Mitchell, Michael; Nogueira, Pedro A S; Lafita-Navarro, M Carmen; Perez-Castro, Lizbeth; Eriom, Joyane; Kilgore, Jessica A; Williams, Noelle S; Guo, Lei; Xu, Lin; Conacci-Sorrell, Maralice.
Afiliação
  • 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.
  • Nogueira PAS; Department of Pediatrics, University of Texas Dell Medical School, Austin, 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 Cell Biology, 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; Department of Biochemistry, 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.
  • Conacci-Sorrell M; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
FEBS J ; 291(10): 2172-2190, 2024 May.
Article em En | MEDLINE | ID: mdl-38431776
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.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Receptores de Hidrocarboneto Arílico / Cinurenina / Neuroblastoma Limite: Humans Idioma: En Revista: FEBS J Assunto da revista: BIOQUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Receptores de Hidrocarboneto Arílico / Cinurenina / Neuroblastoma Limite: Humans Idioma: En Revista: FEBS J Assunto da revista: BIOQUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos