title: Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany. dr.dr.martingrimm@googlemail.com.
authors.forename: M
authors.initials: M
authors.lastname: Grimm
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Calgéer
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: P
authors.initials: P
authors.lastname: Teriete
authors.affiliation: Department of Pathology, University Hospital Tuebingen, Liebermeisterstrasse 8, 72076, Tuebingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Biegner
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Munz
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Reinert
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D008297:Male; D009062:Mouth Neoplasms / Q000201:enzymology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D013831:Thiamine / Q000378:metabolism*; D014174:Transketolase / Q000378:metabolism
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D007655:Ketoglutarate Dehydrogenase Complex; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D014174:Transketolase; D013831:Thiamine
keywords: Oral squamous cell carcinoma; Oxybenfothiamine; Targeted therapy; Thiamine-dependent enzymes; Tumor metabolism