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Valproic acid protects intestinal organoids against radiation via NOTCH signaling
Author(s) -
Park Misun,
Kwon Junhye,
Youk Heejeong,
Shin Ui Sup,
Han YoungHoon,
Kim Younjoo
Publication year - 2021
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.11591
Subject(s) - lgr5 , notch signaling pathway , histone deacetylase , stem cell , cancer research , organoid , pharmacology , histone deacetylase inhibitor , cancer stem cell , radiosensitizer , microbiology and biotechnology , chemistry , biology , signal transduction , radiation therapy , medicine , histone , biochemistry , gene
Radiotherapy is a leading treatment for various types of cancer. However, exposure to high‐dose ionizing radiation causes acute gastrointestinal injury and gastrointestinal syndrome. This has significant implications for human health, and therefore, radioprotection is a major area of research. Radiation induces the loss of intestinal stem cells; hence, the protection of stem cells expressing LGR5 (a marker of intestinal epithelial stem cells) is a key strategy for the prevention of radiation‐induced injury. In this study, we identified valproic acid (VPA) as a potent radioprotector using an intestinal organoid culture system. VPA treatment increased the number of LGR5+ stem cells and organoid regeneration after irradiation. N ‐[ N ‐(3,5‐difluorophenacetyl)‐ l ‐alanyl]‐ S ‐phenylglycine t ‐butyl ester (DAPT, an inhibitor of NOTCH signaling) blocked the radioprotective effects of VPA, indicating that NOTCH signaling is a likely mechanism underlying the observed effects of VPA. In addition, VPA acted as a radiosensitizer via the inhibition of histone deacetylase (HDAC) in a colorectal cancer organoid. These results demonstrate that VPA exerts strong protective effects on LGR5+ stem cells via NOTCH signaling and that the inhibition of NOTCH signaling reduces these protective effects, providing a basis for the improved management of radiation injury.