Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma.
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.
Dal Col
Jessica
J
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.
Zancai
Paola
P
Terrin
Liliana
L
Guidoboni
Massimo
M
Ponzoni
Maurilio
M
Pavan
Alessandro
A
Spina
Michele
M
Bergamin
Stefano
S
Rizzo
Silvana
S
Tirelli
Umberto
U
De Rossi
Anita
A
Doglioni
Claudio
C
Dolcetti
Riccardo
R
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
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