glutaminase and Carcinoma--Squamous-Cell

Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. RT increased expression of PMN-MDSC-attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with NFE2L2 mutations.. NFE2L2 mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.

Topics: Animals; Carcinoma, Squamous Cell; Glutaminase; Head and Neck Neoplasms; Humans; Mice; Mutation; Myeloid-Derived Suppressor Cells; NF-E2-Related Factor 2; Radiation Tolerance; Squamous Cell Carcinoma of Head and Neck

Identifying contexts in which cancer cells become addicted to specific nutrients is critical for developing targeted metabolic therapies. In this issue of Cancer Cell, Momcilovic et al. report that suppressed glycolysis following mTOR inhibition is countered by adaptive glutamine catabolism in lung squamous cell carcinoma, sensitizing tumors to glutaminase inhibition.

Topics: Carcinoma, Squamous Cell; Glutaminase; Glutamine; Glycogen Synthase Kinase 3; Humans; Lung Neoplasms

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.

Topics: Amino Acid Transport System ASC; Animals; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Squamous Cell; Female; Gene Expression Regulation, Neoplastic; Glutaminase; Glutamine; Humans; Immunohistochemistry; Middle Aged; Minor Histocompatibility Antigens; Mouth Mucosa; Mouth Neoplasms; Oxidoreductases Acting on CH-CH Group Donors; Real-Time Polymerase Chain Reaction; RNA, Neoplasm

Mice bearing the Lewis lung carcinoma showed a high tumour glutaminase activity and significantly higher concentrations of most amino acids than in both the liver and the skeletal muscle of the host. Tumour tissue slices showed a marked preference for glutamine, especially for oxidation of its skeleton to CO2. It is proposed that the metabolism of this particular carcinoma is focused on amino acid degradation, glutamine being its preferred substrate.

Topics: Amino Acids; Animals; Carcinoma, Squamous Cell; Glucose; Glutaminase; Lipid Metabolism; Liver; Lung Neoplasms; Mice; Mice, Inbred C57BL; Muscles; Neoplasm Transplantation; Proteins

Topics: Alanine Transaminase; Amino Acids; Aspartate Aminotransferases; Carbohydrate Metabolism; Carcinoma, Squamous Cell; Cervix Uteri; Female; Fructose-Bisphosphate Aldolase; Glucosephosphate Dehydrogenase; Glutamate Dehydrogenase; Glutaminase; Humans; Hydro-Lyases; Isocitrate Dehydrogenase; Oxygen Consumption; Uterine Cervical Neoplasms; Uterine Cervicitis

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Animals; Carcinoma; Carcinoma, Squamous Cell; Glutaminase; Humans; Hydrogen-Ion Concentration; Isoenzymes; Kidney; Kinetics; Liver; Lung; Lung Neoplasms; Mitosis; Neoplasm Metastasis; Organometallic Compounds; Phosphates; Rats; Species Specificity

Topics: Adenocarcinoma; Adenoma; Animals; Carcinoma 256, Walker; Carcinoma, Squamous Cell; Fibrosarcoma; Glutaminase; Growth; Mammary Neoplasms, Experimental; Mathematics; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Osteosarcoma; Rats; Time Factors