Next Article in Journal
Diet as a Potential Moderator for Genome Stability and Immune Response in Pediatric Leukemia
Previous Article in Journal
Reviving the Autopsy for Modern Cancer Evolution Research
Article

Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells

1
Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany
2
Center for Biological Systems Analysis (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany
3
Faculty of Biology, University of Freiburg, Schänzlestrasse 1, 79104 Freiburg, Germany
4
Department of Oncology and Children’s Research Center, University Children’s Hospital, Steinwiessstrasse 75, 8032 Zürich, Switzerland
5
Institute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, 79104 Freiburg, Germany
6
German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
7
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany
8
Signaling Research Center BIOSS and CIBSS, University of Freiburg, Schänzlestrasse 18, 79104 Freiburg, Germany
9
Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany
10
Comprehensive Cancer Centre Freiburg (CCCF), Medical Center-University of Freiburg, Hugstetter Strasse 49, 79106 Freiburg, Germany
11
Spemann Graduate School of Biology and Medicine (SGBM), Albertstraße 19A, 79104 Freiburg, Germany
*
Authors to whom correspondence should be addressed.
Contributed equally.
Cancers 2021, 13(3), 412; https://doi.org/10.3390/cancers13030412
Received: 27 December 2020 / Revised: 18 January 2021 / Accepted: 19 January 2021 / Published: 22 January 2021
(This article belongs to the Section Molecular Cancer Biology)
Cancer cells require amino acids to grow and survive. Amino acid starvation inhibits cancer growth. This study investigates why the non-essential amino acid asparagine is important for cancer growth by examining metabolite composition in asparagine-deprived sarcoma cells compared to control cells with normal asparagine access. Our experiments show that asparagine deprivation results in an imbalance between certain antioxidants and free radicals in the cell. Chemicals which impair the regeneration of antioxidants in the cell augment the growth inhibition caused by asparagine starvation.
Amino acids are integral components of cancer metabolism. The non-essential amino acid asparagine supports the growth and survival of various cancer cell types. Here, different mass spectrometry approaches were employed to identify lower aspartate levels, higher aspartate/glutamine ratios and lower tricarboxylic acid (TCA) cycle metabolite levels in asparagine-deprived sarcoma cells. Reduced nicotinamide adenine dinucleotide (NAD+)/nicotinamide adenine dinucleotide hydride (NADH) ratios were consistent with redirection of TCA cycle flux and relative electron acceptor deficiency. Elevated lactate/pyruvate ratios may be due to compensatory NAD+ regeneration through increased pyruvate to lactate conversion by lactate dehydrogenase. Supplementation with exogenous pyruvate, which serves as an electron acceptor, restored aspartate levels, NAD+/NADH ratios, lactate/pyruvate ratios and cell growth in asparagine-deprived cells. Chemicals disrupting NAD+ regeneration in the electron transport chain further enhanced the anti-proliferative and pro-apoptotic effects of asparagine depletion. We speculate that reductive stress may be a major contributor to the growth arrest observed in asparagine-starved cells. View Full-Text
Keywords: sarcoma; metabolomics; asparagine starvation; reductive stress sarcoma; metabolomics; asparagine starvation; reductive stress
Show Figures

Graphical abstract

MDPI and ACS Style

Bauer, C.; Quante, M.; Breunis, W.B.; Regina, C.; Schneider, M.; Andrieux, G.; Gorka, O.; Groß, O.; Boerries, M.; Kammerer, B.; Hettmer, S. Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells. Cancers 2021, 13, 412. https://doi.org/10.3390/cancers13030412

AMA Style

Bauer C, Quante M, Breunis WB, Regina C, Schneider M, Andrieux G, Gorka O, Groß O, Boerries M, Kammerer B, Hettmer S. Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells. Cancers. 2021; 13(3):412. https://doi.org/10.3390/cancers13030412

Chicago/Turabian Style

Bauer, Christoph, Meret Quante, Willemijn B. Breunis, Carla Regina, Michaela Schneider, Geoffroy Andrieux, Oliver Gorka, Olaf Groß, Melanie Boerries, Bernd Kammerer, and Simone Hettmer. 2021. "Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells" Cancers 13, no. 3: 412. https://doi.org/10.3390/cancers13030412

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop