Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies

Lerner, Adam; Epstein, Paul M.

doi:10.1042/bj20051368

Cited by 105 publications

(111 citation statements)

References 288 publications

(321 reference statements)

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…Precise regulation of intracellular cAMP is crucial for this ubiquitous second messenger to control a wide variety of cellular functions, including cell proliferation and differentiation (2), cell metabolism (2), memory formation (5), cardiac contractility (4), and immune responses (1,3). It has been shown that expression of specific isoforms, subcellular localization, and differential regulation of ACs greatly contribute to the diverse and tissue-specific regulation of cAMP (33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang

Collins

Davis

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Regulation of intracellular cAMP by multiple pathways enables differential function of this ubiquitous second messenger in a context-dependent manner. Modulation of G s -stimulated intracellular cAMP has long been known to be modulated by the G i and G q /Ca 2؉ pathways. Recently, the G 13 pathway was also shown to facilitate cAMP responses in murine macrophage cells. We report here that this synergistic regulation of cAMP synthesis by the G s and G 13 pathways is mediated by a specific isoform of adenylyl cyclase, AC7. Furthermore, this signaling paradigm exists in several hematopoietic lineages and can be recapitulated by exogenous expression of AC7 in HEK 293 cells. Mechanistic characterization of this synergistic interaction indicates that it occurs downstream of receptor activation and it can be mediated by the ␣ subunit of either G 12 or G 13 . Our results demonstrate that AC7 is a specific downstream effector of the G 12/13 pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang

Collins

Davis

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Second, the presence of neurotrophin receptors including TrkB has been reported on tumor cells and implicated in malignancy (Desmet and Peeper, 2006). However, cAMP may have anticancer effects, at least in some neoplastic diseases (Chen et al, 1998;Lerner and Epstein, 2006). Therefore, cAMP signaling may be more selective than BDNF/TrkB in protecting normal components of the nervous system without compromising cancer cell killing.…”

Section: Discussionmentioning

confidence: 99%

Role of Kinase Suppressor of Ras-1 in Neuronal Survival Signaling by Extracellular Signal-Regulated Kinase 1/2

Szatmári¹,

Kalita²,

Kharebava³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

Scaffolding proteins including kinase suppressor of Ras-1 (KSR1) determine specificity of signaling by extracellular signal-regulated kinase 1/2 (ERK1/2), enabling it to couple diverse extracellular stimuli to various cellular responses. The scaffolding protein(s) that contributes to ERK1/2-mediated neuronal survival has not yet been identified. In cultured rat cortical neurons, BDNF activates ERK1/2 to enhance neuronal survival by suppressing DNA damage-or trophic deprivation-induced apoptosis. Here we report that in this system, BDNF increased KSR1 association with activated ERK1/2, whereas KSR1 knockdown with a short hairpin (sh) RNA reduced BDNFmediated activation of ERK1/2 and protection against a DNA-damaging drug, camptothecin (CPT). In contrast, BDNF suppression of trophic deprivation-induced apoptosis was unaffected by shKSR1 although blocked by shERK1/2. Also, overexpression of KSR1 enhanced BDNF protection against CPT. Therefore, KSR1 is specifically involved in antigenotoxic activation of ERK1/2 by BDNF. To test whether KSR1 contributes to ERK1/2 activation by other neuroprotective stimuli, we used a cAMP-elevating drug, forskolin. In cortical neurons, ERK1/2 activation by forskolin was protein kinase A (PKA) dependent but TrkB (receptor tyrosine kinase B) independent and was accompanied by the increased association between KSR1 and active ERK1/2. Forskolin suppressed CPT-induced apoptosis in a KSR1 and ERK1/2-dependent manner. Inhibition of PKA abolished forskolin protection, whereas selective PKA activation resulted in an ERK1/2-and KSR1-mediated decrease in apoptosis. Hence, KSR1 is critical for the antiapoptotic activation of ERK1/2 by BDNF or cAMP/PKA signaling. In addition, these novel data indicate that stimulation of cAMP signaling is a candidate neuroprotective strategy to intervene against neurotoxicity of DNA-damaging agents.

show abstract

“…[14][15][16] Inhibition of PDE4 by the selective inhibitor rolipram is shown to suppress tumor growth and augments the anti-tumor effects of chemotherapy and radiation therapy in medulloblastoma, glioblastoma 17 and in several hematological malignancies. 18 Why PDE4 isoforms are overexpressed in so many different tumor types remains elusive, but like other tumorigenesis factors, PDE4 isoforms may be regulated by changes in hypoxia. Adaptation to hypoxia is critical for tumor cell growth and 1 survival.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies

Cited by 105 publications

References 288 publications

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Role of Kinase Suppressor of Ras-1 in Neuronal Survival Signaling by Extracellular Signal-Regulated Kinase 1/2

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

Contact Info

Product

Resources

About