Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. Am J Pathol 2006 Dec;169(6):2171-80
Date
12/07/2006Pubmed ID
17148679Pubmed Central ID
PMC1762462DOI
10.2353/ajpath.2006.051078Scopus ID
2-s2.0-34248647440 (requires institutional sign-in at Scopus site) 110 CitationsAbstract
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.
Author List
Peponi E, Drakos E, Reyes G, Leventaki V, Rassidakis GZ, Medeiros LJMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingApoptosis
Cell Cycle
Cell Cycle Proteins
Cell Line, Tumor
Down-Regulation
Eukaryotic Initiation Factor-4E
Gene Expression Regulation, Neoplastic
Humans
Lymphoma, Mantle-Cell
Phosphatidylinositol 3-Kinases
Phosphoproteins
Phosphorylation
Protein Kinases
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa
Ribosomal Protein S6 Kinases, 90-kDa
Signal Transduction
TOR Serine-Threonine Kinases
