Rapamycin Extends Life Span in ApcMin/+ Colon Cancer FAP Model

Background We previously showed that lifelong mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) 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.