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Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism

The transcription factor hypoxia-inducible factor 1 (HIF1) is the crucial regulator of
genes that are involved in metabolism under hypoxic conditions, but information regarding the
transcriptional activity of HIF1 in normoxic metabolism is limited. Different tumor cells were treated
under normoxic and hypoxic conditions with various drugs that affect cellular metabolism. HIF1ff
was silenced by siRNA in normoxic/hypoxic tumor cells, before RNA sequencing and bioinformatics
analyses were performed while using the breast cancer cell line MDA-MB-231 as a model. Differentially
expressed genes were further analyzed and validated by qPCR, while the activity of the metabolites
was determined by enzyme assays. Under normoxic conditions, HIF1 activity was significantly
increased by (i) glutamine metabolism, which was associated with the release of ammonium, and
it was decreased by (ii) acetylation via acetyl CoA synthetase (ACSS2) or ATP citrate lyase (ACLY), respectively, and (iii) the presence of L-ascorbic acid, citrate, or acetyl-CoA. Interestingly, acetylsalicylic
acid, ibuprofen, L-ascorbic acid, and citrate each significantly destabilized HIF1ff only under normoxia.
The results from the deep sequence analyses indicated that, in HIF1-siRNA silenced MDA-MB-231
cells, 231 genes under normoxia and 1384 genes under hypoxia were transcriptionally significant
deregulated in a HIF1-dependent manner. Focusing on glycolysis genes, it was confirmed that HIF1
significantly regulated six normoxic and 16 hypoxic glycolysis-associated gene transcripts. However,
the results from the targeted metabolome analyses revealed that HIF1 activity affected neither the
consumption of glucose nor the release of ammonium or lactate; however, it significantly inhibited
the release of the amino acid alanine. This study comprehensively investigated, for the first time,
how normoxic HIF1 is stabilized, and it analyzed the possible function of normoxic HIF1 in the
transcriptome and metabolic processes of tumor cells in a breast cancer cell model. Furthermore, these
data imply that HIF1 compensates for the metabolic outcomes of glutaminolysis and, subsequently,
theWarburg effect might be a direct consequence of the altered amino acid metabolism in tumor cells.

Identiferoai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89255
Date25 January 2024
CreatorsKappler, Matthias, Pabst, Ulrike, Weinholdt, Claus, Taubert, Helge, Rot, Swetlana, Kaune, Tom, Kotrba, Johanna, Porsch, Martin, Güttler, Antje, Bache, Matthias, Krohn, Knut, Bull, Fabian, Riemann, Anne, Wickenhauser, Claudia, Seliger, Barbara, Schubert, Johannes, Al-Nawas, Bilal, Thews, Oliver, Grosse, Ivo, Vordermark, Dirk, Eckert, Alexander W.
PublisherMDPI
Source SetsHochschulschriftenserver (HSSS) der SLUB Dresden
LanguageEnglish
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text
Rightsinfo:eu-repo/semantics/openAccess
Relation4742

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