Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status
Open Access
- 30 June 2011
- Vol. 118 (3), 711-721
- https://doi.org/10.1002/cncr.26321
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. Cancer 2012;. © 2011 American Cancer Society.Keywords
This publication has 36 references indexed in Scilit:
- Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cellsCancer, 2011
- Development and implementation of standardized respiratory chain spectrophotometric assays for clinical diagnosisMitochondrion, 2009
- Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patientsRadiotherapy and Oncology, 2009
- Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasisBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2009
- Understanding the Warburg Effect: The Metabolic Requirements of Cell ProliferationScience, 2009
- IDH1andIDH2Mutations in GliomasNew England Journal of Medicine, 2009
- Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer CellsPublished by Elsevier BV ,2008
- TP53Mutations and Survival in Squamous-Cell Carcinoma of the Head and NeckNew England Journal of Medicine, 2007
- Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neckProceedings of the National Academy of Sciences of the United States of America, 2007
- DNA fluorometric assay in 96-well tissue culture plates using Hoechst 33258 after cell lysis by freezing in distilled waterAnalytical Biochemistry, 1990