title: Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status.
abstract: BACKGROUND
  Mutations in the tumor protein 53 (TP53) tumor suppressor gene are common in head and neck squamous cell carcinoma (HNSCC) and correlate with radioresistance. Currently, there are no clinically available therapeutic approaches targeting p53 in HNSCC. In this report, the authors propose a strategy that uses TP53 mutational status to individualize antimetabolic strategies for the potentiation of radiation toxicity in HNSCC cells.
  
  
  METHODS
  Glycolytic flux and mitochondrial respiration were evaluated in wild-type (wt) and mutant (mut) TP53 HNSCC cell lines. Sensitivity to external-beam radiation (XRT) was measured using a clonogenic assay.
  
  
  RESULTS
  HNSCC cells that expressed mutTP53 demonstrated radioresistance compared with HNSCC cells that expressed wtTP53. Glycolytic inhibition potentiated radiation toxicity in mutTP53-expressing, but not wtTP53-expressing, HNSCC cells. The relative sensitivity of mutTP53 HNSCC cells to glycolytic inhibition was caused by a glycolytic dependence associated with decreased mitochondrial complex II and IV activity. The wtTP53-expressing cells maintained mitochondrial reserves and were relatively insensitive to glycolytic inhibition. Inhibition of respiration using metformin increased glycolytic dependence in wtTP53-expressing cells and potentiated the effects of glycolyic inhibition on radiation toxicity.
  
  
  CONCLUSIONS
  TP53 mutation in HNSCC cells was correlated with a metabolic shift away from mitochondrial respiration toward glycolysis, resulting in increased sensitivity to the potentiating effects of glycolytic inhibition on radiation toxicity. In contrast, wtTP53-expressing cells required inhibition of both mitochondrial respiration and glycolysis to become sensitized to radiation. Therefore, the authors concluded that TP53 mutational status may be used as a marker of altered tumor cell metabolism to individualize HNSCC treatment selection of specific, targeted metabolic agents that can overcome cellular resistance to radiation therapy.
authors: Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors: Vlad C
authors: VC
authors: Sandulache
authors: Heath D
authors: HD
authors: Skinner
authors: Thomas J
authors: TJ
authors: Ow
authors: Aijun
authors: A
authors: Zhang
authors: Xuefeng
authors: X
authors: Xia
authors: James M
authors: JM
authors: Luchak
authors: Lee-Jun C
authors: LJ
authors: Wong
authors: Curtis R
authors: CR
authors: Pickering
authors: Ge
authors: G
authors: Zhou
authors: Jeffrey N
authors: JN
authors: Myers
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002588:Cesium Radioisotopes / Q000627:therapeutic use; D003847:Deoxyglucose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010101:Oxygen Consumption / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002588:Cesium Radioisotopes; D007004:Hypoglycemic Agents; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003847:Deoxyglucose