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

Jessica Dal Col, Paola Zancai, Liliana Terrin, Massimo Guidoboni, Maurilio Ponzoni, Alessandro Pavan, Michele Spina, Stefano Bergamin, Silvana Rizzo, Umberto Tirelli, Anita De Rossi, Claudio Doglioni, Riccardo Dolcetti

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)5142-5151
Number of pages10
JournalBlood
Volume111
Issue number10
DOIs
Publication statusPublished - May 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

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