Synergy between Prkdc and Trp53 regulates stem cell proliferation and GI-ARS after irradiation.

Autor: Gurley KE; Division of Human Biology Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle WA 98109, USA., Ashley AK; Department of Chemistry and Biochemistry New Mexico State University, 1780 East University Avenue, Las Cruces, NM 88003, USA., Moser RD; Division of Human Biology Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle WA 98109, USA., Kemp CJ; Division of Human Biology Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle WA 98109, USA.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2017 Nov; Vol. 24 (11), pp. 1853-1860. Date of Electronic Publication: 2017 Jul 07.
DOI: 10.1038/cdd.2017.107
Abstrakt: Ionizing radiation (IR) is one of the most widely used treatments for cancer. However, acute damage to the gastrointestinal tract or gastrointestinal acute radiation syndrome (GI-ARS) is a major dose-limiting side effect, and the mechanisms that underlie this remain unclear. Here we use mouse models to explore the relative roles of DNA repair, apoptosis, and cell cycle arrest in radiation response. IR induces DNA double strand breaks and DNA-PK mutant Prkdc scid/scid mice are sensitive to GI-ARS due to an inability to repair these breaks. IR also activates the tumor suppressor p53 to trigger apoptotic cell death within intestinal crypt cells and p53 deficient mice are resistant to apoptosis. To determine if DNA-PK and p53 interact to govern radiosensitivity, we compared the response of single and compound mutant mice to 8 Gy IR. Compound mutant Prkdc scid/scid /Trp53 -/- mice died earliest due to severe GI-ARS. While both Prkdc scid/scid and Prkdc scid/scid /Trp53 -/- mutant mice had higher levels of IR-induced DNA damage, particularly within the stem cell compartment of the intestinal crypt, in Prkdc scid/scid /Trp53 -/- mice these damaged cells abnormally progressed through the cell cycle resulting in mitotic cell death. This led to a loss of Paneth cells and a failure to regenerate the differentiated epithelial cells required for intestinal function. IR-induced apoptosis did not correlate with radiosensitivity. Overall, these data reveal that DNA repair, mediated by DNA-PK, and cell cycle arrest, mediated by p53, cooperate to protect the stem cell niche after DNA damage, suggesting combination approaches to modulate both pathways may be beneficial to reduce GI-ARS. As many cancers harbor p53 mutations, this also suggests targeting DNA-PK may be effective to enhance sensitivity of p53 mutant tumors to radiation.
Databáze: MEDLINE
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