@article{a592b0c250ed4589b1d7a2d16589fa37,
title = "Rapamycin Extends Life Span in ApcMin/+ Colon Cancer FAP Model",
abstract = "Background: We previously showed that lifelong rapamycin treatment of short-lived ApcMin/+ mice, a model for familial adenomatous polyposis, resulted in a normal lifespan. ApcMin/+ mice develop colon polyps with a low frequency but can be converted to a colon cancer model by dextran sodium sulfate (DSS) treatments (ApcMin/+-DSS model). Materials and Methods: We asked, what effect would pretreatment of ApcMin/+ mice with chronic rapamycin prior to DSS exposure have on survival and colonic neoplasia? Results: Forty-two ppm enteric formulation of rapamycin diet exacerbated the temporary weight loss associated with DSS treatment in both sexes. However, our survival studies showed that chronic rapamycin treatment significantly extended lifespan of ApcMin/+-DSS mice (both sexes) by reductions in colon neoplasia and prevention of anemia. Rapamycin also had prophylactic effects on colon neoplasia induced by azoxymethane and DSS in C57BL/6 males and females. Immunoblot assays showed the expected inhibition of complex 1 of mechanistic or mammalian target of rapamycin (mTORC1) and effectors (S6K→rpS6 and S6K→eEF2K→eEF2) in colon by lifelong rapamycin treatments. To address the question of cell types affected by chronic enteric rapamycin treatment, immunohistochemistry analyses demonstrated that crypt cells had a prominent reduction in rpS6 phosphorylation and increase in eEF2 phosphorylation relative controls. Conclusion: These data indicate that enteric rapamycin prevents or delays colon neoplasia in ApcMin/+-DSS mice through inhibition of mTORC1 in the crypt cells.",
keywords = "Aging, Crypt stem cells, eEF2K, mTORC1, rpS6",
author = "Manish Parihar and Dodds, {Sherry G.} and Gene Hubbard and Javors, {Martin A.} and Randy Strong and Paul Hasty and Sharp, {Zelton Dave}",
note = "Funding Information: The authors thank the excellent technical service provided by Belinda A. Fernandez for the AOM/DSS experiments and Greg Friesenhahn for rapamycin measurements. Drs Teresa Marple and Valarie B. Holcomb provided valuable assistance with tissue harvesting. The authors would also like to acknowledge the UT Health Histology and Immunohistochemistry Core Laboratory for histology preparations, and San Antonio Nathan Shock Aging Animal Models and Longevity Assessment Core for animal care. This study was funded by: National Institutes of Health R01- CA193835 (ZDS); National Institutes of Health (R01 CA188032-01, P01AG017242-17A1) (PH); P01AG017242-17A1; U01AG022307-16; VA 1 I01 BX001641-05A1 (RS). Funding Information: The authors thank the excellent technical service provided by Belinda A. Fernandez for the AOM/DSS experiments and Greg Friesenhahn for rapamycin measurements. Drs Teresa Marple and Valarie B. Holcomb provided valuable assistance with tissue harvesting. The authors would also like to acknowledge the UT Health Histology and Immunohistochemistry Core Laboratory for histology preparations, and San Antonio Nathan Shock Aging Animal Models and Longevity Assessment Core for animal care. This study was funded by: National Institutes of Health R01- CA193835 (ZDS); National Institutes of Health ( R01 CA188032-01 , P01AG017242-17A1 ) (PH); P01AG017242-17A1 ; U01AG022307-16 ; VA 1 I01 BX001641-05A1 (RS). Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = mar,
doi = "10.1016/j.clcc.2020.08.006",
language = "English (US)",
volume = "20",
pages = "e61--e70",
journal = "Clinical Colorectal Cancer",
issn = "1533-0028",
publisher = "Elsevier",
number = "1",
}