Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

// Valeriana Cesarini 1, * , Maurizio Martini 2, * , Lucia Ricci Vitiani 3 , Giovanni Luca Gravina 4 , Silvia Di Agostino 5 , Grazia Graziani 6 , Quintino Giorgio D’Alessandris 7 , Roberto Pallini 7 , Luigi M. Larocca 2 , Pellegrino Rossi 1 , Emmanuele A. Jannini 6 , Susanna Dolci 1 1 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy 2 Institute of Pathological Anatomy, Catholic University of Rome, Rome, Italy 3 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita (ISS), Rome, Italy 4 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy 5 Regina Elena National Cancer Institute-IFO, Oncogenomic and Epigenetic Unit, Rome, Italy 6 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy 7 Department of Neurosurgery, Catholic University of Rome, Rome, Italy * These authors have contributed equally to this work Correspondence to: Susanna Dolci, email: dolci@uniroma2.it Keywords: PDE5, PARP, glioblastoma, MYPT, MMP2 Received: May 24, 2016 Accepted: December 12, 2016 Published: January 14, 2017 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.