TY - JOUR
T1 - Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival
AU - Tinkum, Kelsey L.
AU - Stemler, Kristina M.
AU - White, Lynn S.
AU - Loza, Andrew J.
AU - Jeter-Jones, Sabrina
AU - Michalski, Basia M.
AU - Kuzmicki, Catherine
AU - Pless, Robert
AU - Stappenbeck, Thaddeus S.
AU - Piwnica-Worms, David
AU - Piwnica-Worms, Helen
N1 - Funding Information:
We thank Hiroyuki Mioyshi and Sofia Origanti for technical support and advice throughout the course of the study; Erin Smith and Lynne Collins for technical assistance in harvesting organs; all members of both the H.P.-W. and D.P.-W. laboratories and the T.S.S. laboratory for their input throughout the course of this study; and the Genome Technology Access Center at Washington University for help with genomic analysis. This study was supported in part by Grant P50 CA94056 to the Washington University-MD Anderson Cancer Center Inter-institutional Molecular Imaging Center; Grant P30 NS057105 to Washington University; Department of Defense Prostate Cancer Research Program Training Award Grant PC101951 (to K.L.T.); NIH National Institute of General Medical Sciences (NIGMS) Grant T32GM007200 (to A.J.L.); and NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) Grant T32EB018266 (to A.J.L.). The Genome Technology Access Center is partially supported by National Cancer Institute Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center and by Institute for Clinical and Translational Science/Clinical and Translational Science Award UL1RR024992 from the National Center for Research Resources, a component of the National Institutes of Health, and National Institutes of Health Roadmap for Medical Research. H.P.-W. is a Research Professor of the American Cancer Society.
PY - 2015/12/22
Y1 - 2015/12/22
N2 - Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to highdose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.
AB - Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to highdose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.
KW - Chemotherapy
KW - DNA damage
KW - Fasting
KW - Stem cells
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U2 - 10.1073/pnas.1509249112
DO - 10.1073/pnas.1509249112
M3 - Article
C2 - 26644583
AN - SCOPUS:84952674037
SN - 0027-8424
VL - 112
SP - E7148-E7154
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
ER -