Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

V. Cesarini, M. Martini, L. R. Vitiani, G. L. Gravina, S. Di Agostino, G. Graziani, Q. G. D'Alessandris, R. Pallini, L. M. Larocca, P. Rossi, E. A. Jannini, S. Dolci

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)13223-13239
Number of pages17
JournalOncotarget
Volume8
Issue number8
DOIs
Publication statusPublished - Feb 21 2017

Fingerprint

Type 5 Cyclic Nucleotide Phosphodiesterases
Glioblastoma
Cyclic GMP-Dependent Protein Kinases
Cell Survival
Matrix Metalloproteinases
DNA Repair
DNA Damage
Phenotype
Neoplasms
Poly(ADP-ribose) Polymerases
Ionizing Radiation
Radio
Brain Neoplasms
Adenosine Diphosphate
Cell Movement
Carcinogenesis
Peptide Hydrolases
Radiotherapy
Pharmacology
Drug Therapy

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Blotting, Western
  • Brain Neoplasms/enzymology/genetics/therapy
  • Cell Line, Tumor
  • Cell Survival/genetics/radiation effects
  • Cyclic GMP-Dependent Protein Kinases/metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5/genetics/metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma/enzymology/genetics/therapy
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Matrix Metalloproteinase 2/metabolism
  • Middle Aged
  • Neoplasm Invasiveness
  • Poly(ADP-ribose) Polymerases/metabolism
  • RNA Interference
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome
  • MMP2
  • MYPT
  • PARP
  • PDE5
  • glioblastoma

Cite this

Cesarini, V., Martini, M., Vitiani, L. R., Gravina, G. L., Agostino, S. D., Graziani, G., ... Dolci, S. (2017). Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. Oncotarget, 8(8), 13223-13239. https://doi.org/10.18632/oncotarget.14656 [doi]

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. / Cesarini, V.; Martini, M.; Vitiani, L. R.; Gravina, G. L.; Agostino, S. Di; Graziani, G.; D'Alessandris, Q. G.; Pallini, R.; Larocca, L. M.; Rossi, P.; Jannini, E. A.; Dolci, S.

In: Oncotarget, Vol. 8, No. 8, 21.02.2017, p. 13223-13239.

Research output: Contribution to journalArticle

Cesarini, V, Martini, M, Vitiani, LR, Gravina, GL, Agostino, SD, Graziani, G, D'Alessandris, QG, Pallini, R, Larocca, LM, Rossi, P, Jannini, EA & Dolci, S 2017, 'Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome', Oncotarget, vol. 8, no. 8, pp. 13223-13239. https://doi.org/10.18632/oncotarget.14656 [doi]
Cesarini V, Martini M, Vitiani LR, Gravina GL, Agostino SD, Graziani G et al. Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. Oncotarget. 2017 Feb 21;8(8):13223-13239. https://doi.org/10.18632/oncotarget.14656 [doi]
Cesarini, V. ; Martini, M. ; Vitiani, L. R. ; Gravina, G. L. ; Agostino, S. Di ; Graziani, G. ; D'Alessandris, Q. G. ; Pallini, R. ; Larocca, L. M. ; Rossi, P. ; Jannini, E. A. ; Dolci, S. / Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. In: Oncotarget. 2017 ; Vol. 8, No. 8. pp. 13223-13239.
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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.",
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AU - Gravina, G. L.

AU - Agostino, S. Di

AU - Graziani, G.

AU - D'Alessandris, Q. G.

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AU - Larocca, L. M.

AU - Rossi, P.

AU - Jannini, E. A.

AU - Dolci, S.

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N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Blotting, Western

KW - Brain Neoplasms/enzymology/genetics/therapy

KW - Cell Line, Tumor

KW - Cell Survival/genetics/radiation effects

KW - Cyclic GMP-Dependent Protein Kinases/metabolism

KW - Cyclic Nucleotide Phosphodiesterases, Type 5/genetics/metabolism

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Glioblastoma/enzymology/genetics/therapy

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Matrix Metalloproteinase 2/metabolism

KW - Middle Aged

KW - Neoplasm Invasiveness

KW - Poly(ADP-ribose) Polymerases/metabolism

KW - RNA Interference

KW - Retrospective Studies

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Treatment Outcome

KW - MMP2

KW - MYPT

KW - PARP

KW - PDE5

KW - glioblastoma

U2 - 10.18632/oncotarget.14656 [doi]

DO - 10.18632/oncotarget.14656 [doi]

M3 - Article

VL - 8

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JF - Oncotarget

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