Mantle cell lymphoma (MCL) is characterized by the t(11;14) and
cyclin D1 overexpression. However, additional molecular events are most likely required for
oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that
mammalian target of rapamycin (mTOR) is activated in MCL and contributes to
tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the
phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6
kinase, and p-
ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of
cyclin D1 and the
anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific
short interfering RNA decreased phosphorylation of mTOR signaling
proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic
initiation factor (
eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL
tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-
ribosomal protein S6. Total
eIF4E binding protein 1 and
eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL
tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and
tumor cell survival in MCL.