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

Medientyp: E-Artikel

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

Beteiligte: Kappler, Matthias [Verfasser:in]; Pabst, Ulrike [Verfasser:in]; Weinholdt, Claus [Verfasser:in]; Taubert, Helge [Verfasser:in]; Rot, Swetlana [Verfasser:in]; Kaune, Tom [Verfasser:in]; Kotrba, Johanna [Verfasser:in]; Porsch, Martin [Verfasser:in]; Güttler, Antje [Verfasser:in]; Bache, Matthias [Verfasser:in]; Krohn, Knut [Verfasser:in]; Bull, Fabian [Verfasser:in]; Riemann, Anne [Verfasser:in]; Wickenhauser, Claudia [Verfasser:in]; Seliger, Barbara [Verfasser:in]; Schubert, Johannes [Verfasser:in]; Al-Nawas, Bilal [Verfasser:in]; Thews, Oliver [Verfasser:in]; Grosse, Ivo [Verfasser:in]; Vordermark, Dirk [Verfasser:in]; Eckert, Alexander W. [Verfasser:in]

Erschienen: Basel: MDPI, [2024]

Sprache: Englisch

Schlagwörter: Warburg effect ; tumor ; normoxia ; hypoxia ; glutaminolysis ; glutamine ; HIF1 ; L-ascorbic acid ; metabolism ; glycolysis ; acetylsalicylic acid

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Beschreibung: The transcription factor hypoxia-inducible factor 1 (HIF1) is the crucial regulator ofgenes that are involved in metabolism under hypoxic conditions, but information regarding thetranscriptional activity of HIF1 in normoxic metabolism is limited. Different tumor cells were treatedunder normoxic and hypoxic conditions with various drugs that affect cellular metabolism. HIF1ffwas silenced by siRNA in normoxic/hypoxic tumor cells, before RNA sequencing and bioinformaticsanalyses were performed while using the breast cancer cell line MDA-MB-231 as a model. Differentiallyexpressed genes were further analyzed and validated by qPCR, while the activity of the metaboliteswas determined by enzyme assays. Under normoxic conditions, HIF1 activity was significantlyincreased by (i) glutamine metabolism, which was associated with the release of ammonium, andit 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, acetylsalicylicacid, 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-231cells, 231 genes under normoxia and 1384 genes under hypoxia were transcriptionally significantderegulated in a HIF1-dependent manner. Focusing on glycolysis genes, it was confirmed that HIF1significantly regulated six normoxic and 16 hypoxic glycolysis-associated gene transcripts. However,the results from the targeted metabolome analyses revealed that HIF1 activity affected neither theconsumption of glucose nor the release of ammonium or lactate; however, it significantly inhibitedthe 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 thetranscriptome and metabolic processes of tumor cells in a breast cancer cell model. Furthermore, thesedata 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.

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