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EMBO J. 2018 Jul 13;37(14). pii: e98597. doi: 10.15252/embj.201798597. Epub 2018 Jun 6.

Metabolic vulnerability of cisplatin-resistant cancers.

Obrist F1,2,3,4,5,6, Michels J1,2,3,4,5,6,7, Durand S2,3,4,5,6, Chery A2,3,4,5,6, Pol J2,3,4,5,6, Levesque S1,2,3,4,5,6, Joseph A2,3,4,5,6, Astesana V2,3,4,5,6,8, Pietrocola F2,3,4,5,6, Wu GS9, Castedo M10,3,4,5,6, Kroemer G10,3,4,5,6,11,12.

Author information

1
Faculty of Medicine, University of Paris Sud, Kremlin-Bicêtre, France.
2
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
3
Centre de Recherche des Cordeliers, Equipe 11 labellisée Ligue Nationale Contre le Cancer, Paris, France.
4
Institut National de la Santé et de la Recherche Médicale, U1138, Equipe labellisée Ligue Nationale Contre le Cancer, Villejuif, France.
5
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
6
Université Pierre et Marie Curie, Paris, France.
7
Department of Medical Oncology, Gustave Roussy Comprehensive Cancer Center, Villejuif Paris-Sud University, Villejuif, France.
8
Department of Biology and Biotechnology L. Spallanzani, University of Pavia, Pavia, Italy.
9
Departments of Oncology and Pathology, Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
10
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France marie.castedo-delrieu@gustaveroussy.fr kroemer@orange.fr.
11
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
12
Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.

KEYWORDS:

antimetabolites; cell metabolism; chemotherapy; glutamine; nucleotide

PMID:
29875130
PMCID:
PMC6043854
[Available on 2019-07-13]
DOI:
10.15252/embj.201798597
[Indexed for MEDLINE]

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