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Normoxic accumulation of HIF1α is associated with glutaminolysis

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Abstract

Objectives

The stabilization of the transcription factor and prognostic tumor marker hypoxia-inducible factor 1α (HIF1α) is considered to be crucial for cellular metabolic adaptations to hypoxia. However, HIF1α has also been shown to accumulate under normoxic conditions, although this phenomenon is poorly understood.

Methods

We investigated the conditions for normoxic HIF1α stabilization in different tumor cell lines (e.g., two mammary carcinoma cell lines and three oral squamous cell carcinoma cell lines) via Western blot analysis or immunohistochemical staining. The transcriptional activity of HIF1 was demonstrated by analyzing the messenger RNA (mRNA) expression of the HIF1 target carbonic anhydrase 9 (CA9) via PCR.

Results

Our data demonstrate that the combined incubation of tumor cells with glutamine and growth factors (e.g., EGF, insulin, and serum) mediates the normoxic accumulation of HIF1α in vitro. Consequently, the inhibition of glutaminolysis by a glutaminase inhibitor blocked the normoxic accumulation of HIF1α. Additionally, the normoxic HIF1α protein displayed nuclear translocation and transcriptional activity, which was confirmed by the induction of CA9 mRNA expression. Furthermore, the normoxic accumulation of HIF1α was associated with impaired proliferation of tumor cells. Finally, ammonia, the toxic waste product of glutaminolysis, induced a normoxic accumulation of HIF1α to the same extent as glutamine.

Conclusion

Our study suggests that HIF1α is involved in the regulation of glutamine metabolism and the cellular levels of the toxic metabolic waste product ammonia under normoxia. Hence, our results, together with data presented in the literature, support the hypothesis that HIF1α and its target genes play a crucial role in metabolic pathways, such as glutaminolysis and glycolysis, under both hypoxic and normoxic conditions.

Clinical relevance

Therefore, the inhibition of HIF1α (and/or HIF1α target genes) could emerge as a promising therapeutic approach that would result in the accumulation of toxic metabolic waste products in tumor cells as well as the reduction of their nutrition and energy supply.

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Acknowledgments

We thank our colleagues from the Department of Oral and Maxillofacial Plastic Surgery and the Department of Radiotherapy for their continuous support. We thank S. Hanke and Dr. T. Klapperstück for assistance in cell cycle analysis. We would like to thank NPGLE Support Team (Pamela F, Jacqueline C., Man-Tsuey T. and Leann B., Briana V., Denise R.) for providing English language editing for our manuscript. M.K. was supported by the Wilhelm-Roux-Programm of BMBF/NBL3 (FKZ: 21/25, 24/19, 27/22).

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097, Halle(S), Germany

    Matthias Kappler, Ulrike Pabst, Swetlana Rot, Henri Wichmann, Johannes Schubert & Alexander W. Eckert

  2. Department of Urology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany

    Helge Taubert

  3. Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Halle(S), Germany

    Matthias Bache & Dirk Vordermark

  4. Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle(S), Germany

    Claus Weinholdt & Ivo Grosse

  5. Institute of Legal Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany

    Uta-Dorothee Immel

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  1. Matthias Kappler
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Correspondence to Matthias Kappler.

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The work was supported by the Wilhelm-Roux-Programm of BMBF/NBL3 (FKZ: 21/25, 24/19, 27/22).

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Matthias Kappler, Ulrike Pabst, Dirk Vordermark, and Alexander W. Eckert contributed equally to this work.

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Kappler, M., Pabst, U., Rot, S. et al. Normoxic accumulation of HIF1α is associated with glutaminolysis. Clin Oral Invest 21, 211–224 (2017). https://doi.org/10.1007/s00784-016-1780-9

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