title: Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage.
abstract: In this study, everolimus (RAD001) was used to determine the role of mammalian target of rapamycin (mTOR) in hepatocarcinogenesis. We show that RAD001 effectively inhibits proliferation of hepatocytes during chronic liver injury. Remarkably, the ability of RAD001 to impair cell cycle progression requires activation of the DNA damage response; loss of p53 significantly attenuates the antiproliferative effects of mTOR inhibition. RAD001 modulates the expression of specific cell cycle-related proteins and the assembly of cyclin-cyclin-dependent kinase complexes to prevent cell cycle progression. Furthermore, RAD001 sustains the apoptosis sensitivity of hepatocytes during chronic liver injury by inhibiting p53-induced p21 expression. Long-term treatment with RAD001 markedly delays DNA damage-induced liver tumor development.
  
  
  CONCLUSIONS
  We provide evidence that mTOR inhibition has a substantial effect on sequential carcinogenesis and may offer an effective strategy to delay liver tumor development in patients at risk.
authors.affiliation: Clinic of Hepatology, Gastroenterology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Laura Elisa
authors.initials: LE
authors.lastname: Buitrago-Molina
authors.forename: Deepika
authors.initials: D
authors.lastname: Pothiraju
authors.forename: Jutta
authors.initials: J
authors.lastname: Lamlé
authors.forename: Silke
authors.initials: S
authors.lastname: Marhenke
authors.forename: Uta
authors.initials: U
authors.lastname: Kossatz
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Nisar
authors.initials: N
authors.lastname: Malek
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D000068338:Everolimus; D022781:Hepatocytes / Q000187:drug effects*; D006867:Hydrolases / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D016159:Tumor Suppressor Protein p53; D000068338:Everolimus; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D006867:Hydrolases; C020156:fumarylacetoacetase; D020123:Sirolimus