Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model.
Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder with a predisposition to gastrointestinal polyposis and cancer. Hyperactivation of mTOR-signaling has been associated with PJS. We previously reported that rapamycin treatment of Lkb1(+/-) mice after the onset of polyposis reduced the polyp burden. Here we evaluated the preventive efficacy of rapamycin on Peutz-Jeghers polyposis. We found that rapamycin treatment of Lkb1(+/-) mice initiated before the onset of polyposis in Lkb1(+/-) mice led to a dramatic reduction in both polyp burden and polyp size and this reduction was associated with decreased phosphorylation levels of S6 and 4EBP1. Together, these findings support the use of rapamycin as an option for chemoprevention and treatment of PJS.
Wei
Chongjuan
C
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA.
Amos
Christopher I
CI
Zhang
Nianxiang
N
Zhu
Jing
J
Wang
Xiaopei
X
Frazier
Marsha L
ML
D055372:AMP-Activated Protein Kinases; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000502:physiology; D004195:Disease Models, Animal; D018095:Germ-Line Mutation; D007417:Intestinal Polyps / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus