Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model

Abstract

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.

Figures

Fig. 1

Rapamycin treatment reduces polyp burden in Lkb1+/− mice. (A) Comparison of polyp size distribution in control and rapamycin-treated mice, shown as the treated/control ratio for the indicated size categories (diameter in mm). (B) The mean tumor burdens were 1996.7 ± 440 mm3 in control mice and 218.7 ± 52 mm3 in rapamycin-treated mice (14 mice in each group; P < 0.001, Student's t-test).

Fig. 2

Rapamycin treatment decreases the phosphorylation level of S6 and 4EBP1 of Lkb1+/− polyps. (A and B) Representative H&E staining of the polyps from control (A) and rapamycin-treated (B) mice; original magnification, ×40. (C and D) Representative anti-phospho-S6 immunostaining of polyps sections from control (C) and rapamycin-treated (D) mice; original magnification ×200. (E) Polyp lysates from the control group (lanes 1 and 2) and the rapamycin-treated group (lanes 3 and 4) were subjected to western blotting with anti-phospho-S6 (Ser235/236) antibody (p-S6), anti-phospho-4EBP1 (Thr70) antibody [p-4EBP1 (Thr70)], and anti-phospho-4EBP1 (Ser65) antibody [p-4EBP1 (Ser65)], with anti-actin antibody (Actin) and /or anti-S6 antibody (S6) as a loading control.