Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo.

• 影响指数: 4.46
• 发表时间: 01 2020 15
• 来源期刊: Toxicol Appl Pharmacol
• DOI: 10.1016/j.taap.2019.114855
• PMID: 31830491
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 生物
• 作者列表: Li M,Lang Y,Gu MM,Shi J,Chen BPC,Yu L,Zhou PK,Shang ZF

关键词: DNA damage; DNA-PKcs; Mitotic catastrophe; Radiation-induced intestinal injuries; VND3207

Mesh: Animals; Apoptosis / drug effects radiation effects; Benzaldehydes / pharmacology; Cell Line, Tumor; Cell Proliferation / drug effects radiation effects; Cyclic GMP-Dependent Protein Kinase Type I / metabolism; DNA-Activated Protein Kinase / genetics metabolism; Epithelial Cells / drug effects pathology radiation effects; Gamma Rays / adverse effects; Humans; Intestinal Mucosa / cytology drug effects pathology radiation effects; Loss of Function Mutation; Male; Mice; Phosphorylation / drug effects; Radiation Injuries, Experimental / pathology prevention & control; Radiation-Protective Agents / pharmacology therapeutic use

Abstract

Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without γ-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of γH2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.