A systems oncology approach identifies NT5E as a key metabolic regulator in tumor cells and modulator of platinum sensitivity

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Title: A systems oncology approach identifies NT5E as a key metabolic regulator in tumor cells and modulator of platinum sensitivity
Author(s): Nevedomskaya, E
Perryman, R
Solanki, S
Syed, N
Mayboroda, OA
Keun, HC
Item Type: Journal Article
Abstract: Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5′-nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.
Publication Date: 2-Dec-2015
Date of Acceptance: 2-Dec-2015
URI: http://hdl.handle.net/10044/1/46045
DOI: https://dx.doi.org/10.1021/acs.jproteome.5b00793
ISSN: 1535-3893
Publisher: American Chemical Society
Start Page: 280
End Page: 290
Journal / Book Title: Journal of Proteome Research
Volume: 15
Issue: 1
Copyright Statement: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Proteome Research, copyright © 2015 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
Sponsor/Funder: Brain Tumour Research Campaign
Funder's Grant Number: n/a
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemical Research Methods
Biochemistry & Molecular Biology
O2PLS
chemometrics
cancer
metabonomics
transcriptomics
data integration
chemotherapy
cisplatin resistance
HUMAN BREAST-CANCER
DNA COPY NUMBER
OVARIAN-CANCER
MESENCHYMAL TRANSITION
POOR-PROGNOSIS
CD73
EXPRESSION
ADENOSINE
RECEPTOR
SURVIVAL
O2PLS
cancer
chemometrics
chemotherapy
cisplatin resistance
data integration
metabonomics
transcriptomics
5'-Nucleotidase
Antineoplastic Agents
Carboplatin
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
GPI-Linked Proteins
Gene Expression
Humans
Organoplatinum Compounds
Ovarian Neoplasms
Proportional Hazards Models
Systems Biology
Treatment Outcome
Cell Line, Tumor
Humans
Ovarian Neoplasms
Organoplatinum Compounds
Carboplatin
5'-Nucleotidase
Antineoplastic Agents
Treatment Outcome
Proportional Hazards Models
Systems Biology
Gene Expression
Drug Resistance, Neoplasm
Female
GPI-Linked Proteins
Science & Technology
Life Sciences & Biomedicine
Biochemical Research Methods
Biochemistry & Molecular Biology
O2PLS
chemometrics
cancer
metabonomics
transcriptomics
data integration
chemotherapy
cisplatin resistance
HUMAN BREAST-CANCER
DNA COPY NUMBER
OVARIAN-CANCER
MESENCHYMAL TRANSITION
POOR-PROGNOSIS
CD73
EXPRESSION
ADENOSINE
RECEPTOR
SURVIVAL
Biochemistry & Molecular Biology
06 Biological Sciences
03 Chemical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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