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Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

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Abstract

Purpose

Thiamine-dependent enzymes (TDEs) linking glycolysis with the tricarboxylic acid cycle (TCA) pyruvate dehydrogenase (PDH), of the pentose phosphate pathway transketolases (TKTs), the TCA alpha-ketoglutarate deydrogenase (KGDH)/2-oxoglutarate dehydrogenase (OGDH) complex, and the amino acid catabolism branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex are crucial factors for tumor metabolism. The expression of these enzymes has not been analyzed for carcinogenesis of oral squamous cell carcinoma (OSCC) with special focus on new targeted metabolic therapies as yet.

Methods

TDEs PDH, KGDH (OGDH), and BCKDH were analyzed in normal oral mucosa (n = 14), oral precursor lesions (simple hyperplasia, n = 21; squamous intraepithelial neoplasia, SIN I–III, n = 35), and OSCC specimen (n = 46) by immunohistochemistry and western blot (WB) analysis in OSCC tumor cell lines.

Results

Although the total numbers of PDH and KGDH (OGDH) positive samples decreased in OSCC, both enzymes were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue. BCKDH has been demonstrated to be significantly overexpressed in the carcinogenesis of OSCC. Specificity of the antibodies was confirmed by WB analysis.

Conclusions

This is the first study showing increased expression of TDEs in OSCC. Metabolic targeting of TDEs (including TKTs) by antagonistic compounds like oxythiamine or oxybenfothiamine 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

PDH:

Pyruvate dehydrogenase

PPP:

Pentose phosphate pathway

TKT:

Transketolase

TCA:

Tricarboxylic acid cycle

KGDH:

Ketoglutarate dehydrogenase

OGDH:

2-oxoglutarate deydrogenase

BCKDH:

Branched-chain alpha-ketoacid dehydrogenase

TCA:

Tricarboxylic acid cycle

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Acknowledgments

We thank Julia Grimm for her technical assistance.

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Authors and Affiliations

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

    M. Grimm, B. Calgéer, A. Munz & S. Reinert

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

    P. Teriete

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

    T. Biegner

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  1. M. Grimm
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  5. A. Munz
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Correspondence to M. Grimm.

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Grimm, M., Calgéer, B., Teriete, P. et al. Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?. Clin Transl Oncol 18, 196–205 (2016). https://doi.org/10.1007/s12094-015-1352-5

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