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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-10-3208. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3208v1 101/10/4122    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Moon, E.-Y. Articles by Lerner, A. Search for Related Content PubMed PubMed Citation Articles by Moon, E.-Y. Articles by Lerner, A. Related Collections Neoplasia Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 May 2003, Vol. 101, No. 10, pp. 4122-4130 NEOPLASIA PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia cells that is regulated by protein phosphatase 2A Eun-Yi Moon and Adam Lerner From the Evans Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA; and the Department of Pathology, Boston University School of Medicine, Boston, MA. Chronic lymphocytic leukemia (CLL) cells, but not peripheral blood T cells, undergo apoptosis following treatment with inhibitors of type 4 cyclic nucleotide phosphodiesterase (PDE4), a process that correlates dose dependently with elevation of adenosine 3',5'-cyclic monophosphate (cAMP) in leukemic cells. We show that treatment of CLL cells with rolipram, a prototypic PDE4 inhibitor, and forskolin, an adenylate cyclase activator, induces mitochondrial depolarization, release of cytochrome c into the cytosol, caspase-9 and -3 activation, and cleavage of poly(adenosine diphosphate [ADP]-ribose)polymerase. Inhibitors of caspase-9, but not caspase-8, block rolipram/forskolin-induced CLL apoptosis. In a subset of CLL patients, B-cell lymphoma 2 (Bcl-2)-associated death promoter homolog (Bad), a proapoptotic Bcl-2 family member that when phosphorylated on specific serine residues is sequestered in the cytosol by 14-3-3, was dephosphorylated at Ser112 following rolipram/forskolin treatment of leukemic cells. Rolipram/forskolin treatment also induced Bad to accumulate in CLL heavy-membrane fractions, consistent with Bad translocation to mitochondria. To determine the mechanism for rolipram/forskolin-induced Bad dephosphorylation, we examined CLL phosphatase activity. Rolipram/forskolin treatment augmented protein phosphatase 2A (PP2A) activity, as well as levels of immunoreactive PP2A catalytic subunit. Treatment of CLL cells with a concentration of okadaic acid (5 nM) that selectively inhibits PP2A, reduced both rolipram/forskolin-induced mitochondrial cytochrome c release and mitochondrial depolarization. Okadaic acid restored Bad Ser112 phosphorylation and Bad association with 14-3-3 in rolipram/forskolin-treated CLL cells. These results suggest that PDE4 inhibitors may induce CLL apoptosis by activating PP2A-induced dephosphorylation of proapoptotic BH3-only Bcl-2 family members such as Bad. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Kumar, S. Kostin, J.-P. Flacke, H. P. Reusch, and Y. Ladilov Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells J. Biol. Chem., May 29, 2009; 284(22): 14760 - 14768. [Abstract] [Full Text] [PDF] J. A. Meyers, D. W. Su, and A. Lerner Chronic Lymphocytic Leukemia and B and T Cells Differ in Their Response to Cyclic Nucleotide Phosphodiesterase Inhibitors J. Immunol., May 1, 2009; 182(9): 5400 - 5411. [Abstract] [Full Text] [PDF] L. Zhang, F. Murray, A. Zahno, J. R. Kanter, D. Chou, R. Suda, M. Fenlon, L. Rassenti, H. Cottam, T. J. Kipps, et al. Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia PNAS, December 9, 2008; 105(49): 19532 - 19537. [Abstract] [Full Text] [PDF] G. Levallet, J. Levallet, and P.-J. Bonnamy FSH-induced phosphoprotein phosphatase 2A-mediated deactivation of particulate phosphodiesterase-4 activities is abolished after alteration in proteoglycan synthesis in immature rat Sertoli cells J. Endocrinol., April 1, 2008; 197(1): 45 - 54. [Abstract] [Full Text] [PDF] J. A. Meyers, J. Taverna, J. Chaves, A. Makkinje, and A. Lerner Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells Clin. Cancer Res., August 15, 2007; 13(16): 4920 - 4927. [Abstract] [Full Text] [PDF] R. Rotem, A. Heyfets, O. Fingrut, D. Blickstein, M. Shaklai, and E. Flescher Jasmonates: Novel Anticancer Agents Acting Directly and Selectively on Human Cancer Cell Mitochondria Cancer Res., March 1, 2005; 65(5): 1984 - 1993. [Abstract] [Full Text] [PDF] P. G. Smith, F. Wang, K. N. Wilkinson, K. J. Savage, U. Klein, D. S. Neuberg, G. Bollag, M. A. Shipp, and R. C. T. Aguiar The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma Blood, January 1, 2005; 105(1): 308 - 316. [Abstract] [Full Text] [PDF] E. Parrella, M. Gianni', V. Cecconi, E. Nigro, M. M. Barzago, A. Rambaldi, C. Rochette-Egly, M. Terao, and E. Garattini Phosphodiesterase IV Inhibition by Piclamilast Potentiates the Cytodifferentiating Action of Retinoids in Myeloid Leukemia Cells: CROSS-TALK BETWEEN THE cAMP AND THE RETINOIC ACID SIGNALING PATHWAYS J. Biol. Chem., October 1, 2004; 279(40): 42026 - 42040. [Abstract] [Full Text] [PDF] S. Tiwari, K. Felekkis, E.-Y. Moon, A. Flies, D. H. Sherr, and A. Lerner Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis Blood, April 1, 2004; 103(7): 2661 - 2667. [Abstract] [Full Text] [PDF] D. T. Jones, E. Addison, J. M. North, M. W. Lowdell, A. V. Hoffbrand, A. B. Mehta, K. Ganeshaguru, N. I. Folarin, and R. G. Wickremasinghe Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs Blood, March 1, 2004; 103(5): 1855 - 1861. [Abstract] [Full Text] [PDF] J. Arp, M. G. Kirchhof, M. L. Baroja, S. H. Nazarian, T. A. Chau, C. A. Strathdee, E. H. Ball, and J. Madrenas Regulation of T-Cell Activation by Phosphodiesterase 4B2 Requires Its Dynamic Redistribution during Immunological Synapse Formation Mol. Cell. Biol., November 15, 2003; 23(22): 8042 - 8057. [Abstract] [Full Text] [PDF]

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