A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells.
Jianfeng LiSilvia GaravagliaZhaofeng YeAndrea MorettiOlga V BelyaevaAlison BeiserMd IbrahimAnna WilkSteve McClellanAlla V KlyuyevaKelli R GoggansNatalia Y KedishviliE Alan SalterAndrzej WierzbickiMarie E MigaudSteven J MullettNathan A YatesCarlos J CamachoMenico RizziRobert William SobolPublished in: Communications biology (2021)
Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs may regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent, and selective inhibitors of key ALDH enzymes may represent a novel CSC-directed treatment paradigm for ALDH + cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, our structure of human ALDH1A3 combined with in silico modeling identifies a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis reveals that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation.
Keyphrases
- stem cells
- cell proliferation
- binding protein
- mass spectrometry
- endothelial cells
- mild cognitive impairment
- squamous cell carcinoma
- gene expression
- bone marrow
- mesenchymal stem cells
- small molecule
- high resolution
- young adults
- papillary thyroid
- poor prognosis
- cell cycle
- long non coding rna
- cell therapy
- combination therapy
- lymph node metastasis
- molecular dynamics simulations