Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Sci Transl Med. 2020 Feb 19;12(531). doi: 10.1126/scitranslmed.aax8694.
-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in -amplified NB.
扩增神经母细胞瘤（NB）的预后较差，直接针对 MYCN 的治疗效果一直具有挑战性。在这里，我们发现醛脱氢酶家族 18 成员 A1（ALDH18A1）对 NB 细胞的增殖、自我更新和致瘤性有深远的影响，是 NB 患者，尤其是扩增型患者的一个潜在风险因素。机制研究表明，ALDH18A1 可以在转录和转录后水平上调节 MYCN 的表达，而 MYCN 则反向激活 ALDH18A1，从而形成正反馈回路。通过分子对接和筛选，我们鉴定出一种 ALDH18A1 特异性抑制剂 YG1702，并证明药理抑制 ALDH18A1 足以诱导增殖减少的表型，并在 NB 异种移植模型中导致肿瘤消退和延长生存，为破坏这种扩增型 NB 中的相互调节回路提供了治疗思路。
