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Glutaminolysis and carcinogenesis of oral squamous cell carcinoma

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Abstract

Glutaminolysis is a crucial factor for tumor metabolism in the carcinogenesis of several tumors but has not been clarified for oral squamous cell carcinoma (OSCC) yet. Expression of glutaminolysis-related solute carrier family 1, member 5 (SLC1A5)/neutral amino acid transporter (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLDH) was analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I–III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry. SLC1A5/ASCT2 and GLS were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue, while GLDH was weakly detected. Compared with SIN I–III SLC1A5/ASCT2 and GLS expression were significantly increased in OSCC. GLDH expression did not significantly differ from SIN I–III compared with OSCC. This study shows the first evidence of glutaminolysis-related SLC1A5/ASCT2, GLS, and GLDH expression in OSCC. The very weak GLDH expression indicates that glutamine metabolism is rather related to nucleotide or protein/hexosamine biosynthesis or to the function as an antioxidant (glutathione) than to energy production or generation of lactate through entering the tricarboxylic acid cycle. Overcoming glutaminolysis by targeting c-Myc oncogene (e.g. by natural compounds) and thereby cross-activation of mammalian target of rapamycin complex 1 or SLC1A5/ASCT2, GLS inhibitors may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

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Abbreviations

SIN:

Squamous intraepithelial neoplasia

OSCC:

Oral squamous cell carcinoma

SLC1A5:

Solute carrier family 1, member 5

GLS:

Glutaminase

GLDH:

Glutamate dehydrogenase

TCA:

Tricarboxylic acid cycle

mTOR:

Mammalian target of rapamycin

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Acknowledgments

We thank Julia Grimm for her technical assistance.

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The authors have no competing interests.

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany

    Marcel Cetindis, Adelheid Munz, Siegmar Reinert & Martin Grimm

  2. Department of Pathology, University Hospital Tuebingen, Liebermeisterstrasse 8, 72076, Tuebingen, Germany

    Thorsten Biegner

  3. Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Peter Teriete

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  1. Marcel Cetindis
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  2. Thorsten Biegner
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  3. Adelheid Munz
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  5. Siegmar Reinert
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Correspondence to Martin Grimm.

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Cetindis, M., Biegner, T., Munz, A. et al. Glutaminolysis and carcinogenesis of oral squamous cell carcinoma. Eur Arch Otorhinolaryngol 273, 495–503 (2016). https://doi.org/10.1007/s00405-015-3543-7

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