SIRT1 inhibitors mitigate radiation-induced GI syndrome by enhancing intestinal-stem-cell survival

Guoxiang Fu, Shengzhi Chen, Liping Liang, Xiaomeng Li, Peiyuan Tang, Xinxin Rao, Mengxue Pan, Xiaoya Xu, Yuanchuang Li, Ye Yao, Yi Zhou, Jun Gao, Shaobo Mo, Sanjun Cai, Junjie Peng, Zhen Zhang, Hans Clevers, Jianjun Gao, Guoqiang Hua

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.

Original languageEnglish
Pages (from-to)20-30
Number of pages11
JournalCancer letters
Volume501
DOIs
Publication statusPublished - 31 Mar 2021

Keywords

  • Acetylation
  • Animals
  • Cell Survival/drug effects
  • Gastrointestinal Diseases/drug therapy
  • Histone Deacetylase Inhibitors/pharmacology
  • Humans
  • Intestinal Mucosa/drug effects
  • Intestines/drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Niacinamide/pharmacology
  • Organoids
  • Radiation Injuries, Experimental/drug therapy
  • Sirtuin 1/antagonists & inhibitors
  • Tumor Suppressor Protein p53/metabolism

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