Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status

Vlad C. Sandulache, Heath D. Skinner, Thomas J. Ow, Aijun Zhang, Xuefeng Xia, James M. Luchak, Lee Jun C Wong, Curtis R. Pickering, Ge Zhou, Jeffrey N. Myers

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)711-721
Number of pages11
JournalCancer
Volume118
Issue number3
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

Fingerprint

Radiation
Neoplasms
Proteins
Respiration
Glycolysis
Carcinoma, squamous cell of head and neck
Mutation
Metformin
Mutant Proteins
Tumor Biomarkers
Tumor Suppressor Genes
Radiotherapy
Cell Line
Therapeutics

Keywords

  • 2-deoxyglucose
  • metformin
  • mitochondria
  • p53
  • radiation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status. / Sandulache, Vlad C.; Skinner, Heath D.; Ow, Thomas J.; Zhang, Aijun; Xia, Xuefeng; Luchak, James M.; Wong, Lee Jun C; Pickering, Curtis R.; Zhou, Ge; Myers, Jeffrey N.

In: Cancer, Vol. 118, No. 3, 01.02.2012, p. 711-721.

Research output: Contribution to journalArticle

Sandulache, VC, Skinner, HD, Ow, TJ, Zhang, A, Xia, X, Luchak, JM, Wong, LJC, Pickering, CR, Zhou, G & Myers, JN 2012, 'Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status', Cancer, vol. 118, no. 3, pp. 711-721. https://doi.org/10.1002/cncr.26321
Sandulache, Vlad C. ; Skinner, Heath D. ; Ow, Thomas J. ; Zhang, Aijun ; Xia, Xuefeng ; Luchak, James M. ; Wong, Lee Jun C ; Pickering, Curtis R. ; Zhou, Ge ; Myers, Jeffrey N. / Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status. In: Cancer. 2012 ; Vol. 118, No. 3. pp. 711-721.
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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.",
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AU - Skinner, Heath D.

AU - Ow, Thomas J.

AU - Zhang, Aijun

AU - Xia, Xuefeng

AU - Luchak, James M.

AU - Wong, Lee Jun C

AU - Pickering, Curtis R.

AU - Zhou, Ge

AU - Myers, Jeffrey N.

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N2 - 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.

AB - 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.

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