Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia

Zhang, Lingzhi; Murray, Fiona; Zahno, Anja; Kanter, Joan R.; Chou, Daisy; Suda, Ryan; Fenlon, Michael; Rassenti, Laura Z.; Cottam, Howard B.; Kipps, Thomas J.; Insel, Paul A.

doi:10.1073/pnas.0806152105

Cited by 92 publications

(93 citation statements)

References 45 publications

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“…These data indicate that these PDEs do not contribute significant cAMP hydrolysis in DLBCL. In addition, in agreement with earlier work, 18,19 but contrary to a recent report in chronic lymphoid leukemia (CLL), 20 we found that PDE7B is not expressed in lymphoid cells (DLBCL) and that the PDE7-specific inhibitor BRL-50481 is largely ineffective in DLBCL cell lines (data not shown). These data suggested that the observed cAMP-mediated inhibition of SYK is directly controlled by PDE4B expression/activity.…”

Section: Camp Inhibits Syk Activity In Normal B Cellssupporting

confidence: 93%

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Kim

Rai

McKeller

et al. 2009

Blood

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Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gainand loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued. (Blood. 2009;113: 6153-6160)

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Section: Camp Inhibits Syk Activity In Normal B Cellssupporting

confidence: 93%

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Kim

Rai

McKeller

et al. 2009

Blood

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“…Expression of PDE7B mRNA and protein in peripheral blood mononuclear cells from patients with chronic lymphocytic leukemia is greatly increased compared with cells from healthy individuals (428). PDE7B activity accounts for a greater portion of the cAMP-hydrolyzing activity in these cells, whereas levels of mRNA for PDEs 3B and 4D are reduced.…”

Section: Regulation Of Pde7mentioning

confidence: 91%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

567

546

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The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

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“…[4][5][6][7] The impairment of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) generation by regulation of phosphodiesterases (PDEs) has been implicated in various cancer pathologies. 8,9 PDEs are enzymes that regulate cellular levels of cAMP/cGMP by controlling their degradation. These enzymes are classified into 11 families (PDE1-PDE11) based on their sequence similarity, substrate preference and sensitivity to various inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF

et al. 2012

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Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated. We exposed 10 different lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we analyzed various in silico predicted hypoxia-responsive elements (p-HREs) found in PDE4A and PDE4D genes. Performing mutation analysis of the p-HRE in luciferase reporter constructs, we identified four functional HRE sites in the PDE4A gene and two functional HRE sites in the PDE4D gene that mediated hypoxic induction of the reporter. Silencing of hypoxia-inducible factor subunits (HIF1a and HIF2a) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i) as a cyclic adenosine monophosphate (cAMP) -elevating agent, cAMP analogs or protein kinase A (PKA)-modulating drugs and an exchange protein directly activated by cAMP (EPAC) activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis enhanced HIF signaling as measured by HRE reporter gene assay, HIF and HIF target genes expression ((lactate dehydrogenase A), LDHA, (pyruvate dehydrogenase kinase 1) PDK1 and (vascular endothelial growth factor A) VEGFA). Notably, inhibition of PDE4 by PDE4i or silencing of PDE4A and PDE4D reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation. Moreover, PDE4i treatment reduced hypoxia-induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. Our findings suggest that PDE4 is expressed in lung cancer, crosstalks with HIF signaling and promotes lung cancer progression. Thus, PDE4 may represent a therapeutic target for lung cancer therapy.

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Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia

Cited by 92 publications

References 45 publications

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF

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