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Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome.

ABSTRACT: Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients. Furthermore, silencing of endogenous PDE5 by short hairpin lentiviral transduction (sh-PDE5) in the T98G GBM cell line induced activation of an invasive phenotype. Similarly, pharmacological inhibition of PDE5 activity strongly enhanced cell motility and invasiveness in T98G cells. This invasive phenotype was accompanied by increased secretion of metallo-proteinase 2 (MMP-2) and activation of protein kinase G (PKG). Moreover, PDE5 silencing markedly enhanced DNA damage repair and cell survival following irradiation. The enhanced radio-resistance of sh-PDE5 GBM cells was mediated by an increase of poly(ADP-ribosyl)ation (PARylation) of cellular proteins and could be counteracted by poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, PDE5 overexpression in PDE5-negative U87G cells significantly reduced MMP-2 secretion, inhibited their invasive potential and interfered with DNA damage repair and cell survival following irradiation. These studies identify PDE5 as a favorable prognostic marker for GBM, which negatively affects cell invasiveness and survival to ionizing radiation. Moreover, our work highlights the therapeutic potential of targeting PKG and/or PARP activity in this currently incurable subset of brain cancers.

SUBMITTER: Cesarini V

PROVIDER: S-EPMC5355091 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome.

Cesarini Valeriana V Martini Maurizio M Vitiani Lucia Ricci LR Gravina Giovanni Luca GL Di Agostino Silvia S Graziani Grazia G D'Alessandris Quintino Giorgio QG Pallini Roberto R Larocca Luigi M LM Rossi Pellegrino P Jannini Emmanuele A EA Dolci Susanna S

Oncotarget 20170201 8

Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM ...[more]

PMID: 28099939

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Project description:Congenital glioblastoma multiforme (cGBM) historically has been considered an aggressive tumor of infancy requiring extensive chemotherapy to achieve cure. We report on 4 patients at our institution with cGBMs who were treated with surgery and chemotherapy (carboplatin and etoposide every 21 days for 2-6 cycles). Four of four patients are progression free at a median time of 27.5 months (22-103 months). To characterize the molecular biology of cGBM, we compared the gene expression profiles of 3 cGBMs to 12 pediatric and 6 primary adult glioblastomas collected at our institution. Unsupervised hierarchical clustering showed cGBMs grouped together with other high-grade gliomas. cGBMs demonstrated marked similarity to both pediatric and adult GBMs, with only a total of 31 differentially expressed genes identified (FDR < 0.05). Unique molecular features of congenital GBMs identified included over-expression of multiple genes involved in glucose metabolism and tissue hypoxia pathways. Four tyrosine kinases were also mong the up-regulated genes (RET, RASGRF2, EFNA5, ALK). Thus, at our institution congenital GBMs, while similar both histologically and molecularly to other GBMs, appear to have a good prognosis with surgery in combination with relatively moderate chemotherapy. Further study is needed to determine if the few gene expression differences that were identified may contribute to the better survival seen in these tumors compared to pediatric or adult GBMs. Key Words: glioblastoma; congenital; pediatric; gene expression; microarray Molecular profiling of 18 AT/RT patient tumor samples was performed using Affymetrix U133 Plus2 GeneChips. Data were background corrected and normalized using gcRMA (as implemented in Bioconductor). Unsupervised agglomerative hierarchical clustering was performed to identify subsets of AT/RTs with similar gene expression. Limma (moderated t-tests; Bioconductor) was used to identify signature genes for each cluster. Bioinformatics web tool DAVID was used to identify enriched biological processes for each cluster. Survival was analyzed using Kaplan-Meier curves and Cox Hazard Ratio. Bioinformatics tools Gene Set Enrichment (GSEA) and Ingenuity Pathways Analysis were also used to gain further insight into cluster differences.

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Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome.

Publications

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome.

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