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Cancers (Basel). 2019 Sep 3;11(9). pii: E1298. doi: 10.3390/cancers11091298.

Papillary Renal Cell Carcinomas Rewire Glutathione Metabolism and Are Deficient in Both Anabolic Glucose Synthesis and Oxidative Phosphorylation.

Author information

1
Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Ihnestrasse 63-73, 14195 Berlin, Germany. alahmad@molgen.mpg.de.
2
Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany. alahmad@molgen.mpg.de.
3
Berlin Institute for Urologic Research, Charitéplatz 1, 10117 Berlin, Germany. alahmad@molgen.mpg.de.
4
Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Ihnestrasse 63-73, 14195 Berlin, Germany. vanessa.paffrath@posteo.de.
5
Berlin Institute for Urologic Research, Charitéplatz 1, 10117 Berlin, Germany. vanessa.paffrath@posteo.de.
6
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E.Orabona, 470126 Bari, Italy. rosannaclima@gmail.com.
7
Department of Medical and Surgical Sciences-DIMEC, Medical Genetics Unit, University of Bologna, 40126 Bologna, Italy. rosannaclima@gmail.com.
8
Department of Urology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany. Jonas.Busch@charite.de.
9
Department of Urology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany. Anja.Rabien@charite.de.
10
Institut für Pathologie am Klinikum Leverkusen, Am Gesundheitspark 11, 51375 Leverkusen, Germany. e.kilic@pathologie-leverkusen.de.
11
Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany. e.kilic@pathologie-leverkusen.de.
12
Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany. sonia.villegas@charite.de.
13
Max Planck Institute for Molecular Genetics, Sequencing Core Facility, Ihnestrasse 63-73, 14195 Berlin, Germany. timmerma@molgen.mpg.de.
14
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E.Orabona, 470126 Bari, Italy. marcella.attimonelli@uniba.it.
15
Berlin Institute for Urologic Research, Charitéplatz 1, 10117 Berlin, Germany. klaus.jung@charite.de.
16
Department of Urology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany. klaus.jung@charite.de.
17
Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Ihnestrasse 63-73, 14195 Berlin, Germany. meierhof@molgen.mpg.de.

Abstract

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, profound downregulation of gluconeogenesis and oxidative phosphorylation was observed at the protein level. In contrast, analysis of the The Cancer Genome Atlas (TCGA) papillary RCC cohort revealed no significant change in transcripts encoding oxidative phosphorylation compared to normal kidney tissue, highlighting the importance of proteomic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.

KEYWORDS:

Papillary renal cell carcinoma (pRCC); glutathione metabolism; metabolic reprogramming; metabolome profiling; proteome profiling

PMID:
31484429
DOI:
10.3390/cancers11091298
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