Abstract
Mantle cell lymphoma (MCL) is a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1. A high proportion of MCL tumors harbor wild-type (wt) and potentially functional p53 gene. We show here that stabilization and activation of wt-p53 using a recently developed potent MDM2 inhibitor, nutlin 3A, results in significant p53-dependent G1-S cell cycle arrest and apoptosis in MCL cells through regulation of p53 target genes. As mTOR signaling is activated in MCL and may control cyclin D1 levels, we show that p53 activation may downregulate the AKT/mTOR pathway through a mechanism involving AMP kinase (AMPK). Despite the non-genotoxic mode of nutlin 3A treatment, we show evidence that stabilization of p53 is associated with its phosphorylation at serine 15 residue and activation of AMPK. Stimulation of AMPK kinase activity using AICAR inhibits phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and rpS6. Pharmacologic inhibition of AMPK using compound C in nutlin-3A-treated MCL cells harboring wt-p53 did not affect the level of ser15p-p53, suggesting that the ser15p-p53 → AMPK is the direction involved in the p53/AMPK/mTOR cross talk. These data establish a p53 → AMPK → mTOR mechanism in MCL and uncover a novel biologic effect of potent MDM2 inhibitors in preclinical models of MCL.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007; 445: 661–665.
Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445: 656–660.
Martins CP, Brown-Swigart L, Evan GI . Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006; 127: 1323–1334.
Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004; 428: 332–337.
Wendel HG, Malina A, Zhao Z, Zender L, Kogan SC, Cordon-Cardo C et al. Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res 2006; 66: 7639–7646.
Feng Z, Zhang H, Levine AJ, Jin S . The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005; 102: 8204–8209.
Fernandez V, Hartmann E, Ott G, Campo E, Rosenwald A . Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol 2005; 23: 6364–6369.
Peponi E, Drakos E, Reyes G, Leventaki V, Rassidakis GZ, Medeiros LJ . Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. Am J Pathol 2006; 169: 2171–2180.
Michael D, Oren M . The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol 2003; 13: 49–58.
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–848.
Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci USA 2006; 103: 1888–1893.
Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood 2005; 106: 3150–3159.
Kojima K, Konopleva M, McQueen T, O'Brien S, Plunkett W, Andreeff M . Mdm2 inhibitor nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood 2006; 108: 993–1000.
Drakos E, Thomaides A, Medeiros LJ, Li J, Leventaki V, Konopleva M et al. Inhibition of p53-murine double minute 2 interaction by nutlin-3A stabilizes p53 and induces cell cycle arrest and apoptosis in Hodgkin lymphoma. Clin Cancer Res 2007; 13: 3380–3387.
Jadayel DM, Lukas J, Nacheva E, Bartkova J, Stranks G, De Schouwer PJ 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). Leukemia 1997; 11: 64–72.
Rassidakis GZ, Feretzaki M, Atwell C, Grammatikakis I, Lin Q, Lai R et al. Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 2005; 105: 827–829.
Camps J, Salaverria I, Garcia MJ, Prat E, Beà S, Pole JC et al. Genomic imbalances and patterns of karyotypic variability in mantle-cell lymphoma cell lines. Leuk Res 2006; 30: 923–934.
Lai R, McDonnell TJ, O’Connor SL, Medeiros LJ, Oudat R, Keating M et al. Establishment and characterization of a new mantle cell lymphoma cell line, Mino. Leuk Res 2002; 26: 849–855.
Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 2005; 24: 1348–1358.
Hay N, Sonenberg N . Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926–1945.
Rudelius M, Pittaluga S, Nishizuka S, Pham TH, Fend F, Jaffe ES et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 2006; 108: 1668–1676.
Secchiero P, Barbarotto E, Tiribelli M, Zerbinati C, di Iasio MG, Gonelli A et al. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood 2006; 107: 4122–4129.
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005; 18: 283–293.
Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 2007; 67: 3043–3053.
Acknowledgements
E Drakos performed experiments, analyzed data and contributed to the writing of the manuscript; V Atsaves, Jiang Li and Vasiliki Leventaki performed experiments; M Andreeff and LJ Medeiros contributed to the writing of the manuscript; GZ Rassidakis designed experiments, analyzed data and contributed to the writing of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Drakos, E., Atsaves, V., Li, J. et al. Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. Leukemia 23, 784–790 (2009). https://doi.org/10.1038/leu.2008.348
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2008.348
Keywords
This article is cited by
-
Inhibition of XPO1 with KPT-330 induces autophagy-dependent apoptosis in gallbladder cancer by activating the p53/mTOR pathway
Journal of Translational Medicine (2022)
-
Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics
Oncogenesis (2022)
-
Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Journal of Experimental & Clinical Cancer Research (2021)
-
Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?
Cellular & Molecular Biology Letters (2021)
-
Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA
Journal of Hematology & Oncology (2018)