Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation

Sci Rep. 2015 Apr 10;5:8566. doi: 10.1038/srep08566.

Abstract

Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice. CHIR99021 treatment specifically blocked apoptosis and PUMA induction and K120 acetylation of p53 mediated by acetyl-transferase Tip60, while it had no effect on p53 stabilization, phosphorylation or p21 induction. CHIR99021 also protected human intestinal cultures from radiation by PUMA but not p21 suppression. These results demonstrate that p53 posttranslational modifications play a key role in the pathological and apoptotic response of the intestinal stem cells to radiation and can be targeted pharmacologically.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Gastrointestinal Diseases / etiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / radiation effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Humans
  • Intestines / cytology*
  • Mice
  • Mice, Knockout
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Radiation Injuries, Experimental
  • Radiation Tolerance / drug effects
  • Radiation Tolerance / genetics
  • Radiation, Ionizing*
  • Radiation-Protective Agents / pharmacology*
  • Radiotherapy / adverse effects
  • Receptors, G-Protein-Coupled / metabolism
  • Stem Cells / drug effects*
  • Stem Cells / metabolism*
  • Stem Cells / radiation effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics

Substances

  • Apoptosis Regulatory Proteins
  • Chir 99021
  • Lgr5 protein, mouse
  • PUMA protein, mouse
  • Pyridines
  • Pyrimidines
  • Radiation-Protective Agents
  • Receptors, G-Protein-Coupled
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Glycogen Synthase Kinase 3