Cytidine deaminase deficiency in tumor cells is associated with sensitivity to a naphthol derivative and a decrease in oncometabolite levels - Archive ouverte HAL Access content directly
Journal Articles Cellular and Molecular Life Sciences Year : 2022

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

(1, 2) , (2) , (2) , (3) , (4) , (2) , (3) , (3) , (2)
1
2
3
4

Abstract

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.
Fichier principal
Vignette du fichier
Mameri-CMLS-2022-CC-BY.pdf (2.23 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-03766208 , version 1 (31-08-2022)

Identifiers

Cite

Hamza Mameri, Géraldine Buhagiar-Labarchède, Gaëlle Fontaine, Céline Corcelle, Caroline Barette, et al.. Cytidine deaminase deficiency in tumor cells is associated with sensitivity to a naphthol derivative and a decrease in oncometabolite levels. Cellular and Molecular Life Sciences, 2022, 79 (8), pp.465. ⟨10.1007/s00018-022-04487-9⟩. ⟨hal-03766208⟩
54 View
3 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More