2. Academic Validation
  3. Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth

Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth

  • Sci Transl Med. 2020 Feb 19;12(531):eaax8694. doi: 10.1126/scitranslmed.aax8694.
Yu-Feng Guo 1 2 3,  Jiang-Jie Duan 1 2 3,  Jun Wang 1 2 3,  Lin Li 1 2 3,  Di Wang 1 2 3,  Xun-Zhou Liu 1 2,  Jing Yang 2 3,  Hua-Rong Zhang 2 3,  Jing Lv 1 2 3,  Yong-Jun Yang 1 2 3,  Ze-Yu Yang 1 2 3,  Jiao Cai 1 2 3,  Xue-Mei Liao 1 2 3,  Tao Tang 1 2 3,  Ting-Ting Huang 1 2 3,  Feng Wu 2 3,  Xian-Yan Yang 1 2 3,  Qian Wen 1 2 3,  Xiu-Wu Bian 4 3,  Shi-Cang Yu 5 2 3
Affiliations

Affiliations

  • 1 Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 2 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 3 Key Laboratory of Tumor Immunopathology of the Ministry of Education, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 4 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. [email protected] [email protected].
  • 5 Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. [email protected] [email protected].
PMID: 32075946 DOI: 10.1126/scitranslmed.aax8694
Abstract

MYCN-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 MYCN 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 MYCN-amplified NB.

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