title: Association of cancer metabolism-related proteins with oral carcinogenesis - indications for chemoprevention and metabolic sensitizing of oral squamous cell carcinoma?
abstract: BACKGROUND
  Tumor metabolism is a crucial factor for the carcinogenesis of oral squamous cell carcinoma (OSCC).
  
  
  METHODS
  Expression of IGF-R1, glycolysis-related proteins (GLUT-1, HK 2, PFK-1, LDHA, TKTL1), mitochondrial enzymes (SDHA, SDHB, ATP synthase) were 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 and real-time polymerase chain reaction (qPCR) analysis in OSCC cell lines. Metabolism-related proteins were correlated with proliferation activity (Ki-67) and apoptotic properties (TUNEL assay) in OSCC. Specificity of antibodies was confirmed by western blotting in cancer cell lines.
  
  
  RESULTS
  Expression of IGF-R1, glycolysis-related proteins (GLUT-1, HK 2, LDHA, TKTL1), and mitochondrial enzymes (SDHA, SDHB, ATP synthase) were significantly increased in the carcinogenesis of OSCC. Metabolic active regions of OSCC were strongly correlated with proliferating cancer (Ki-67+) cells without detection of apoptosis (TUNEL assay).
  
  
  CONCLUSIONS
  This study provides the first evidence of the expression of IGF-R1, glycolysis-related proteins GLUT-1, HK 2, PFK-1, LDHA, and TKTL1, as well as mitochondrial enzymes SDHA, SDHB, and ATP synthase in the multi-step carcinogenesis of OSCC. Both, hypoxia-related glucose metabolism and mitochondrial oxidative phosphorylation characteristics are associated with the carcinogenesis of OSCC. Acidosis and OXPHOS may drive a metabolic shift towards the pentose phosphate pathway (PPP). Therefore, inhibition of the PPP, glycolysis, and targeted anti-mitochondrial therapies (ROS generation) by natural compounds or synthetic vitamin derivatives may act as sensitizer for apoptosis in cancer cells mediated by adjuvant therapies in OSCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, Tuebingen 72076, Germany. dr.dr.martingrimm@googlemail.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Grimm
authors.forename: Marcel
authors.initials: M
authors.lastname: Cetindis
authors.forename: Max
authors.initials: M
authors.lastname: Lehmann
authors.forename: Thorsten
authors.initials: T
authors.lastname: Biegner
authors.forename: Adelheid
authors.initials: A
authors.lastname: Munz
authors.forename: Peter
authors.initials: P
authors.lastname: Teriete
authors.forename: Wiebke
authors.initials: W
authors.lastname: Kraut
authors.forename: Siegmar
authors.initials: S
authors.lastname: Reinert
mesh_terms: D000918:Antibody Specificity / Q000276:immunology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018890:Chemoprevention; D053938:DNA Fragmentation; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053858:Metabolic Networks and Pathways; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins