Rapamycin Extends Life Span in Apc^Min/+ Colon Cancer FAP Model

Background: We previously showed that lifelong rapamycin treatment of short-lived Apc^Min/+ mice, a model for familial adenomatous polyposis, resulted in a normal lifespan. Apc^Min/+ mice develop colon polyps with a low frequency but can be converted to a colon cancer model by dextran sodium sulfate (DSS) treatments (Apc^Min/+-DSS model). Materials and Methods: We asked, what effect would pretreatment of Apc^Min/+ 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 Apc^Min/+-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 Apc^Min/+-DSS mice through inhibition of mTORC1 in the crypt cells.