title: Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma.
abstract: Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27(Kip1) inhibitor induced by down-regulation of the p45(Skp2) and Cks1 proteins, which target p27(Kip1) for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico (CRO), Istituto di Ricovero e Cura a Caratiere Scientifico (IRCCS) National Cancer Institute, Aviano, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dal Col
authors.forename: Paola
authors.initials: P
authors.lastname: Zancai
authors.forename: Liliana
authors.initials: L
authors.lastname: Terrin
authors.forename: Massimo
authors.initials: M
authors.lastname: Guidoboni
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pavan
authors.forename: Michele
authors.initials: M
authors.lastname: Spina
authors.forename: Stefano
authors.initials: S
authors.lastname: Bergamin
authors.forename: Silvana
authors.initials: S
authors.lastname: Rizzo
authors.forename: Umberto
authors.initials: U
authors.lastname: Tirelli
authors.forename: Anita
authors.initials: A
authors.lastname: De Rossi
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human