Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Abstract

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 Ser473 p-AKT, 13 of 21 (62%) Ser2448 p-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.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…161,163,164 As mentioned before the Rheb GTPase is an activator of mTORC1. Rheb is highly expressed in some human lymphomas 31,[165][166][167] and other cancers. 168 Rheb activity is dependent on farnesylation.…”

Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma

“…8 Nutlin-3A (Sigma, St Louis, MO, USA), the AMP kinase (AMPK) stimulator AICAR, and the AMPK inhibitor compound C (Calbiochem, San Diego, CA, USA) were used at various concentrations and time points as indicated. MDM2-p53 interaction was inhibited using a racemic mixture of the active and inactive enantiomers, nutlin-3A and nutlin-3B (Sigma), respectively.…”

“…8 Cell proliferation was evaluated using a tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolioum, MTS], the CellTiter 96 aqueous cell proliferation assay (Promega, Madison, WI, USA) and mQuant spectrophotometer (BIO-TEK Instruments Inc., Winooski, VT, USA) according to the manufacturer's protocol. All experiments were repeated at least three times.…”

“…In addition, we recently showed that activation of mTOR signaling contributes to cell cycle and apoptosis deregulation in MCL and controls cyclin D1 expression. 8 The levels and activity of p53 in mammalian cells are critically regulated by its physiologic inhibitor, MDM2 (HDM2 in humans). 9 Nutlin-3A, a recently developed small molecule that disrupts the MDM2-p53 interaction stabilizing and activating p53 protein, has substantial in vitro and in vivo antitumor activity against cancer including hematologic malignancies.…”

Mantle Cell Lymphoma: Decision Making for Transplant

“…Other than overexpression of cyclin D1, activation of mammalian target of rapamycin (mTOR) also plays a major role in growth and proliferation in MCL cells 125 . Inhibitiors of mTOR (rapamycin, temsirolimus, everolimus) may increase apoptosis and decrease proliferation rate by causing G1 arrest in the cell cycle 126 . Single agent temsirolimus has been shown to have clinical activity in phase II trials, and a randomized phase III trial [127][128][129] .…”