Cyclic AMP and cyclic GMP phosphodiesterase activities in Hodgkin's disease lymphocytes

Aleksijevic, A.; Lugnier, Claire; Giron, C; Mayer, S.; Stoclet, Jean‐Claude; Lang, J. M.

doi:10.1016/0192-0561(87)90119-6

Cited by 11 publications

(7 citation statements)

References 23 publications

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“…Interestingly, in MM PDE5A is involved in escape mechanisms of immune responses against tumor cells, an aspect of great importance in the pathology of HL as well (Serafini et al, 2006). Enhanced phosphodiesterase activity and reduced cGMP-levels have been detected in samples of HL patients demonstrating the significance of these enzymes for this disease (Aleksijevic et al, 1983(Aleksijevic et al, , 1987. Our data demonstrate a pathologic mechanism of elevated PDE-activity and suggest, therefore, that treatment with PDE-inhibitors might be a promising therapeutic approach in HL.…”

Section: Discussionmentioning

confidence: 69%

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Nagel

Schneider

Rosenwald

et al. 2011

Genes Chromosomes & Cancer

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Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.

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Section: Discussionmentioning

confidence: 69%

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Nagel

Schneider

Rosenwald

et al. 2011

Genes Chromosomes & Cancer

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“…As described in Table 2, altered expression and/or activity of one or more cyclic nucleotide signaling mediators have been reported in various carcinomas and hematological malignancies [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. The role of cAMP and cGMP signaling and activation of their down-steam effectors (i.e .…”

Section: Cyclic Nucleotide Signaling In Cancermentioning

confidence: 99%

“…Numerous studies have found alterations in cyclic nucleotide signaling in hematological malignancies when compared to nonmalignant hematopoietic cells [46,49,50,66,68,69,70,71,72,73,74,75,76]. Predominantly, these alterations result in an attenuation of cAMP signaling with unaltered or amplified cGMP signaling.…”

Section: Cyclic Nucleotide Signaling In Cancermentioning

confidence: 99%

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Fajardo

Piazza

Tinsley

2014

Cancers

186

169

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For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

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“…Many carcinomas and hematological malignancies have been associated with reduced levels of cAMP and/or cGMP secondary to an elevation in PDE activity [6][7][8][9][10]. Chronic lymphocytic leukemia cells exhibit increased PDE7B expression [11]; PDE5 is strongly expressed in glioblastoma multiforme [12] and colon cancer [13], and glioma cells overexpress one or more isoforms of PDE4 [14].…”

Section: Introductionmentioning

confidence: 99%

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

Pinto

Faucz

Paza³

et al. 2020

Cancers

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Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3′5′-cyclic monophosphate (cAMP) and guanosine 3′5′-cyclic monophosphate (cGMP) to their inactive 5′ monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith–Wiedemann syndrome).

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Cyclic AMP and cyclic GMP phosphodiesterase activities in Hodgkin's disease lymphocytes

Cited by 11 publications

References 23 publications

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

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