TY - JOUR
T1 - Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma
AU - Col, Jessica Dal
AU - Zancai, Paola
AU - Terrin, Liliana
AU - Guidoboni, Massimo
AU - Ponzoni, Maurilio
AU - Pavan, Alessandro
AU - Spina, Michele
AU - Bergamin, Stefano
AU - Rizzo, Silvana
AU - Tirelli, Umberto
AU - De Rossi, Anita
AU - Doglioni, Claudio
AU - Dolcetti, Riccardo
PY - 2008/5/15
Y1 - 2008/5/15
N2 - 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 rapa- mycin (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
Kip1inhibitor 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.
AB - 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 rapa- mycin (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
Kip1inhibitor 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.
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U2 - 10.1182/blood-2007-07-103481
DO - 10.1182/blood-2007-07-103481
M3 - Article
C2 - 18339899
AN - SCOPUS:46749155539
VL - 111
SP - 5142
EP - 5151
JO - Blood
JF - Blood
SN - 0006-4971
IS - 10
ER -