Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma

Dal Col, Jessica, Zancai, Paola, Terrin, Liliana, Guidoboni, Massimo, Ponzoni, Maurilio, Pavan, Alessandro, Spina, Michele, Bergamin, Stefano, Rizzo, Silvana, Tirelli, Umberto, De Rossi, Anita, Doglioni, Claudio and Dolcetti, Riccardo (2008) Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood, 111 10: 5142-5151. doi:10.1182/blood-2007-07-103481


Author Dal Col, Jessica
Zancai, Paola
Terrin, Liliana
Guidoboni, Massimo
Ponzoni, Maurilio
Pavan, Alessandro
Spina, Michele
Bergamin, Stefano
Rizzo, Silvana
Tirelli, Umberto
De Rossi, Anita
Doglioni, Claudio
Dolcetti, Riccardo
Title Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2008-05-15
Sub-type Article (original research)
DOI 10.1182/blood-2007-07-103481
Open Access Status Not yet assessed
Volume 111
Issue 10
Start page 5142
End page 5151
Total pages 10
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Formatted 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 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 p27Kip1 inhibitor induced by down-regulation of the p45Skp2 and Cks1 proteins, which target p27Kip1 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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