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.
摘要：
神经母细胞瘤在临床管理中提出了重大挑战。尽管发病率相对较低，这种恶性肿瘤对癌症相关儿童死亡率的影响不成比例.根据风险分层定制治疗，包括MYCN癌基因扩增，仍然至关重要，然而，高危病例往往面临治疗抵抗和复发。这里,我们探索了芳烃受体（AHR），一种涉及多种生理功能的通用转录因子，例如异种生物反应，免疫调节，和细胞生长。尽管它在恶性肿瘤中的作用各不相同，AHR在神经母细胞瘤中的参与仍然难以捉摸。我们的研究调查了神经母细胞瘤细胞中AHR及其配体犬尿氨酸（Kyn）之间的相互作用。Kyn由色氨酸（Trp）通过吲哚胺2,3-双加氧酶1（IDO1）和色氨酸2,3-双加氧酶（TDO2）的活性产生。我们发现神经母细胞瘤细胞对TDO2抑制剂680C91表现出敏感性，暴露了潜在的脆弱性。此外，将TDO2抑制与视黄酸或伊立替康（两种用于治疗神经母细胞瘤患者的化学治疗剂）组合显示出在选定细胞系中的协同作用。重要的是,使用患者数据的临床相关性分析建立了Kyn-AHR通路基因表达升高与不良预后之间的联系,尤其是年龄较大的儿童。这些发现强调了Kyn-AHR通路在神经母细胞瘤进展中的重要性。强调其作为治疗靶点的潜在作用。
