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A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells.
Li, Jianfeng; Garavaglia, Silvia; Ye, Zhaofeng; Moretti, Andrea; Belyaeva, Olga V; Beiser, Alison; Ibrahim, Md; Wilk, Anna; McClellan, Steve; Klyuyeva, Alla V; Goggans, Kelli R; Kedishvili, Natalia Y; Salter, E Alan; Wierzbicki, Andrzej; Migaud, Marie E; Mullett, Steven J; Yates, Nathan A; Camacho, Carlos J; Rizzi, Menico; Sobol, Robert W.
Afiliação
  • Li J; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
  • Garavaglia S; Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL, 36604, USA.
  • Ye Z; Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy.
  • Moretti A; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • Belyaeva OV; School of Medicine, Tsinghua University, Beijing, China.
  • Beiser A; Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy.
  • Ibrahim M; Structural Plant Biology Laboratory, Department of Botany and Plant Biology, University of Geneva, 1211, Geneva, Switzerland.
  • Wilk A; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 720 20th Street South, Kaul 440B, Birmingham, AL, 35294, USA.
  • McClellan S; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
  • Klyuyeva AV; Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL, 36604, USA.
  • Goggans KR; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
  • Kedishvili NY; Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL, 36604, USA.
  • Salter EA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
  • Wierzbicki A; Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL, 36604, USA.
  • Migaud ME; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
  • Mullett SJ; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 720 20th Street South, Kaul 440B, Birmingham, AL, 35294, USA.
  • Yates NA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 720 20th Street South, Kaul 440B, Birmingham, AL, 35294, USA.
  • Camacho CJ; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 720 20th Street South, Kaul 440B, Birmingham, AL, 35294, USA.
  • Rizzi M; Department of Chemistry, University of South Alabama, 6040 USA South Drive, Mobile, AL, 36688, USA.
  • Sobol RW; Department of Chemistry, University of South Alabama, 6040 USA South Drive, Mobile, AL, 36688, USA.
Commun Biol ; 4(1): 1420, 2021 12 21.
Article em En | MEDLINE | ID: mdl-34934174
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tretinoína / Células-Tronco Neoplásicas / Aldeído Oxirredutases / Glioma Limite: Humans Idioma: En Revista: Commun Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tretinoína / Células-Tronco Neoplásicas / Aldeído Oxirredutases / Glioma Limite: Humans Idioma: En Revista: Commun Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos