title: Glutaminolysis and carcinogenesis of oral squamous cell carcinoma.
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.
authors: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
authors: Marcel
authors: M
authors: Cetindis
authors: Department of Pathology, University Hospital Tuebingen, Liebermeisterstrasse 8, 72076, Tuebingen, Germany.
authors: Thorsten
authors: T
authors: Biegner
authors: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
authors: Adelheid
authors: A
authors: Munz
authors: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors: Peter
authors: P
authors: Teriete
authors: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
authors: Siegmar
authors: S
authors: Reinert
authors: Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany. dr.dr.martingrimm@googlemail.com.
authors: Martin
authors: M
authors: Grimm
mesh_terms: D026962:Amino Acid Transport System ASC / Q000096:biosynthesis; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005972:Glutaminase / Q000096:biosynthesis; D005973:Glutamine / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D026962:Amino Acid Transport System ASC; D014408:Biomarkers, Tumor; D015778:Minor Histocompatibility Antigens; D012334:RNA, Neoplasm; C498848:SLC1A4 protein, human; C420506:SLC1A5 protein, human; D005973:Glutamine; D044925:Oxidoreductases Acting on CH-CH Group Donors; C093910:galactonolactone dehydrogenase; D005972:Glutaminase
keywords: Glutaminolysis; Oral squamous cell carcinoma; Tumor metabolism