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

Yu-Feng Guo1,2,3, Jiang-Jie Duan1,2,3, Jun Wang1,2,3

  • 1Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.

Science Translational Medicine
|February 21, 2020
PubMed

Insights

Aldehyde dehydrogenase family 18 member A1 (ALDH18A1) drives neuroblastoma (NB) growth and is a risk factor, particularly in MYCN-amplified NB. Inhibiting ALDH18A1 shows therapeutic promise for treating this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • MYCN-amplified neuroblastoma (NB) presents a poor prognosis due to challenges in directly targeting MYCN.
  • Aldehyde dehydrogenase family 18 member A1 (ALDH18A1) significantly impacts NB cell proliferation, self-renewal, and tumorigenicity.
  • ALDH18A1 is identified as a potential risk factor in NB patients, especially those with MYCN amplification.

Purpose of the Study:

  • To investigate the role of ALDH18A1 in MYCN-amplified neuroblastoma.
  • To elucidate the regulatory relationship between ALDH18A1 and MYCN.
  • To evaluate the therapeutic potential of targeting ALDH18A1 in NB.

Main Methods:

  • Mechanistic studies to understand ALDH18A1-MYCN interactions.
  • Molecular docking and screening to identify ALDH18A1 inhibitors.
  • In vivo studies using NB xenograft models to assess therapeutic efficacy.

Main Results:

  • ALDH18A1 regulates MYCN expression at both transcriptional and posttranscriptional levels.
  • A positive feedback loop exists where MYCN reciprocally transactivates ALDH18A1.
  • The ALDH18A1 inhibitor YG1702 reduced NB proliferation, induced tumor regression, and prolonged survival in xenograft models.

Conclusions:

  • ALDH18A1 plays a critical role in the progression of MYCN-amplified neuroblastoma.
  • The reciprocal regulatory loop between ALDH18A1 and MYCN is a key driver of NB tumorigenicity.
  • Pharmacological inhibition of ALDH18A1 represents a promising therapeutic strategy for MYCN-amplified NB.

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