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.

[1]  G. Rassidakis,et al.  Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. , 2006, The American journal of pathology.

[2]  E. Jaffe,et al.  Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. , 2006, Blood.

[3]  D. Sabatini,et al.  Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. , 2006, Molecular cell.

[4]  Y. Whang,et al.  Rapamycin inhibits hTERT telomerase mRNA expression, independent of cell cycle arrest. , 2006, Gynecologic oncology.

[5]  Tak W. Mak,et al.  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis , 2006, Nature Reviews Cancer.

[6]  G. Mills,et al.  Inhibition of the phosphatidylinositol‐3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma , 2005, British journal of haematology.

[7]  J. Testa,et al.  Perturbations of the AKT signaling pathway in human cancer , 2005, Oncogene.

[8]  D. Loegering,et al.  Proteomic analysis of mantle-cell lymphoma by protein microarray. , 2005, Blood.

[9]  L. Young,et al.  Constitutive activation of phosphatidyl‐inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR , 2005, The Journal of pathology.

[10]  G. Rassidakis,et al.  Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. , 2005, Blood.

[11]  R. Maestro,et al.  Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma. , 2005, Cancer research.

[12]  J. Y. Kim,et al.  Elevated S-Phase Kinase-Associated Protein 2 Protein Expression in Acute Myelogenous Leukemia , 2004, Clinical Cancer Research.

[13]  S. Kyo,et al.  Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines , 2004, Oncogene.

[14]  Nerea Martínez,et al.  The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. , 2003, Cancer research.

[15]  C. Thompson,et al.  Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. , 2003, Cancer research.

[16]  A. Rebollo,et al.  Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. , 2003, Biochimie.

[17]  Yoo Hong Min,et al.  Phosphatase and tensin homologue phosphorylation in the C‐terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome , 2003, British journal of haematology.

[18]  T. McDonnell,et al.  Characterization of 4 mantle cell lymphoma cell lines. , 2003, Archives of pathology & laboratory medicine.

[19]  A. Zeiher,et al.  Regulation of telomerase activity and anti‐apoptotic function by protein–protein interaction and phosphorylation , 2003, FEBS letters.

[20]  Alfonso Bellacosa,et al.  Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer , 2002, Nature Medicine.

[21]  J. Crespo,et al.  Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. , 2002, Molecular cell.

[22]  K. Anderson,et al.  Cytokines modulate telomerase activity in a human multiple myeloma cell line. , 2002, Cancer research.

[23]  William R. Sellers,et al.  Phosphorylation of the PTEN Tail Acts as an Inhibitory Switch by Preventing Its Recruitment into a Protein Complex* , 2001, The Journal of Biological Chemistry.

[24]  G. Mills,et al.  The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. , 2001, Seminars in oncology.

[25]  H Strohmaier,et al.  A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. , 2001, Molecular cell.

[26]  Brett Larsen,et al.  The cell-cycle regulatory protein Cks1 is required for SCFSkp2-mediated ubiquitinylation of p27 , 2001, Nature Cell Biology.

[27]  L. Chieco‐Bianchi,et al.  Human immunodeficiency virus type 1 modulates telomerase activity in peripheral blood lymphocytes. , 2001, The Journal of infectious diseases.

[28]  Francisca Vazquez,et al.  Phosphorylation of the PTEN Tail Regulates Protein Stability and Function , 2000, Molecular and Cellular Biology.

[29]  M. Quaia,et al.  Retinoic acid induces persistent, RARα‐mediated anti‐proliferative responses in Epstein‐Barr virus–immortalized b lymphoblasts carrying an activated c‐myc oncogene but not in Burkitt's lymphoma cell lines , 2000 .

[30]  R. Medema,et al.  AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 , 2000, Nature.

[31]  L. Chieco‐Bianchi,et al.  Telomerase activity in chronic lymphoproliferative disorders of B‐cell lineage , 1999, British journal of haematology.

[32]  Michele Pagano,et al.  SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 , 1999, Nature Cell Biology.

[33]  S. Do,et al.  Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit* , 1999, The Journal of Biological Chemistry.

[34]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[35]  A. D. Dei Tos,et al.  Cyclin D3 expression in normal, reactive and neoplastic tissues , 1998, The Journal of pathology.

[36]  P. Guldberg,et al.  Alterations of the MMAC1/PTEN gene in lymphoid malignancies. , 1998, Blood.

[37]  H. Müller-Hermelink,et al.  Cyclin D1 expression in mantle cell lymphoma is accompanied by downregulation of cyclin D3 and is not related to the proliferative activity. , 1997, Blood.

[38]  M. Boiocchi,et al.  Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus-immortalized B lymphocytes. , 1996, Blood.

[39]  A. B. Lyons,et al.  Determination of lymphocyte division by flow cytometry. , 1994, Journal of immunological methods.

[40]  C. Peschel,et al.  Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. , 2005, Haematologica.

[41]  G. Mills,et al.  Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. , 2005, Cancer research.

[42]  Huan Yang,et al.  AKT/PKB signaling mechanisms in cancer and chemoresistance. , 2005, Frontiers in bioscience : a journal and virtual library.

[43]  A. Gingras,et al.  mTOR signaling to translation. , 2004, Current topics in microbiology and immunology.

[44]  정준원,et al.  Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome , 2003 .

[45]  J. Slingerland,et al.  PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest , 2002, Nature Medicine.

[46]  J. Larsen,et al.  Soluble CD40 ligand induces selective proliferation of lymphoma cells in primary mantle cell lymphoma cell cultures. , 2000, Blood.

[47]  J. Bartek,et al.  Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin’s lymphomas. Functional studies in a cell line (Granta 519) , 1997, Leukemia.

[48]  A. López-Guillermo,et al.  PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma. , 1994, Blood.