Journal Article

Cytidine deaminase deficiency in tumor cells is associated with sensitivity to a naphthol derivative and a decrease in oncometabolite levels

Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Cancéropôle Ile de France, Ligue Nationale contre le Cancer, Fondation ARC and Curie Cancer (Institut Carnot) , Institut Curie(Innov’booster program, Institut Carnot ), CNRS (Prematuration program ) and Ligue Nationale Contre le Cancer (Comité de l'Essonne)., Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Corcelle, Céline, Mahuteau-Betzer, Florence, Onclercq-Delic, Rosine, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Buhagiar-Labarchède, Géraldine, Beauvineau, Claire, Intégrité du génome, ARN et cancer, Fontaine, Gaëlle, Commissariat à l'énergie atomique et aux énergies alternatives

2022

Overview

Identifying new molecular targets for novel anticancer treatments is a major challenge in clinical cancer research. We have shown that cytidine deaminase (CDA) expression is downregulated in about 60% of cancer cells and tissues. In this study, we aimed to develop a new anticancer treatment specifically inhibiting the growth of CDA-deficient tumor cells. High-throughput screening of a chemical library led to the identification of a naphthol derivative, X55, targeting CDA-deficient tumor cells preferentially, without affecting the growth of non-tumoral cells regardless of CDA expression status. Metabolomic profiling revealed that CDA-deficient HeLa cells differed markedly from control HeLa cells. X55 treatment had a moderate effect on control cells, but greatly disturbed the metabolome of CDA-deficient HeLa cells, worsening the deregulation of many metabolites. In particular, the levels of the three oncometabolites, fumarate, succinate and 2-hydroxyglutarate, were significantly lower in CDA-depleted cells, and this decrease in levels was exacerbated by X55 treatment, revealing an unexpected link between CDA deficiency, mitochondrial function and X55 response. Finally, we identified strong downregulation of MAPT (encoding Tau, a microtubule associated protein) expression as a reliable predictive marker for tumor cell X55 sensitivity.

• Publisher: Springer Verlag,CCSD,Springer International Publishing,Springer Nature B.V
• Subject: Biochemistry / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer research / Cell Biology / Cytidine deaminase / Cytidine Deaminase - genetics / Cytidine Deaminase - metabolism / Deregulation / fumarates / HeLa Cells / High-throughput screening / Humans / Life Sciences / Metabolites / metabolome / Metabolomics / microtubules / Mitochondria / Naphthol / Naphthols / neoplasm cells / neoplasms / Original / Original Article / Sensitivity / succinic acid / Tumor cells / Tumors
• ISBN: 0008362261000