p53-dependent glutamine usage determines susceptibility to oxidative stress in radioresistant head and neck cancer cells

Cell Signal. 2021 Jan:77:109820. doi: 10.1016/j.cellsig.2020.109820. Epub 2020 Oct 31.

Abstract

The manner in which p53 maintains redox homeostasis and the means by which two key metabolic elements, glucose and glutamine, contribute to p53-dependent redox stability remain unclear. To elucidate the manner in which p53 deals with glucose-deprived, reactive oxygen species (ROS)-prone conditions in this regard, two isogenic cancer subclones (HN3R-A and HN3R-B) bearing distinct p53 mutations as an in vitro model of intratumoral p53 heterogeneity were identified. Following cumulative irradiation, the subclones showed a similar metabolic shift to aerobic glycolysis and increasing NADPH biogenesis for cellular defense against oxidative damage irrespective of p53 status. The radioresistant cancer cells became more sensitive to glycolysis-targeting drugs. However, in glucose-deprived and ROS-prone conditions, HN3R-B, the subclone with the original p53 increased the utilization of glutamine by GLS2, thereby maintaining redox homeostasis and ATP. Conversely, HN3R-A, the p53-deficient radioresistant subclone displayed an impairment in glutamine usage and high susceptibility to metabolic stresses as well as ROS-inducing agents despite the increased ROS scavenging system. Collectively, our findings suggest that p53 governs the alternative utilization of metabolic ingredients, such as glucose and glutamine, in ROS-prone conditions. Thus, p53 status may be an important biomarker for selecting cancer treatment strategies, including metabolic drugs and ROS-inducing agents, for recurrent cancers after radiotherapy.

Keywords: Glutamine; Glycolytic shift; Radioresistant cancer cells; Reactive oxygen species; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Glucose / pharmacology
  • Glutaminase / metabolism
  • Glutamine / metabolism*
  • Glutathione / metabolism
  • Glycolysis
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • NADP / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / genetics*
  • Radiation Tolerance
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • Glutamine
  • NADP
  • GLS2 protein, human
  • Glutaminase
  • Glutathione
  • Glucose