Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage.
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.
Buitrago-Molina
Laura Elisa
LE
Clinic of Hepatology, Gastroenterology, and Endocrinology, Hannover Medical School, Hannover, Germany.
Pothiraju
Deepika
D
Lamlé
Jutta
J
Marhenke
Silke
S
Kossatz
Uta
U
Breuhahn
Kai
K
Manns
Michael P
MP
Malek
Nisar
N
Vogel
Arndt
A
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
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