title: Cyclic nucleotide phosphodiesterase-1C (PDE1C) drives cell proliferation, migration and invasion in glioblastoma multiforme cells in vitro.
abstract: Cyclic nucleotides (cAMP & cGMP) are critical intracellular second messengers involved in the transduction of a diverse array of stimuli and their catabolism is mediated by phosphodiesterases (PDEs). We previously detected focal genomic amplification of PDE1C in >90 glioblastoma multiforme (GBM) cells suggesting a potential as a novel therapeutic target in these cells. In this report, we show that genomic gain of PDE1C was associated with increased expression in low passage GBM-derived cell cultures. We demonstrate that PDE1C is essential in driving cell proliferation, migration and invasion in GBM cultures since silencing of this gene significantly mitigates these functions. We also define the mechanistic basis of this functional effect through whole genome expression analysis by identifying down-stream gene effectors of PDE1C which are involved in cell cycle and cell adhesion regulation. In addition, we also demonstrate that Vinpocetine, a general PDE1 inhibitor, can also attenuate proliferation with no effect on invasion/migration. Up-regulation of at least one of this gene set (IL8, CXCL2, FOSB, NFE2L3, SUB1, SORBS2, WNT5A, and MMP1) in TCGA GBM cohorts is associated with worse outcome and PDE1C silencing down-regulated their expression, thus also indicating potential to influence patient survival. Therefore we conclude that proliferation, migration, and invasion of GBM cells could also be regulated downstream of PDE1C.
authors.affiliation: Brain Tumour Research Centre, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Farjana B
authors.initials: FB
authors.lastname: Rowther
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Weinbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: Lancashire Teaching Hospitals, Royal Preston Hospital, Preston, UK.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dawson
authors.affiliation: Lancashire Teaching Hospitals, Royal Preston Hospital, Preston, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Ashton
authors.affiliation: Brain Tumour Research Centre, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Anushree
authors.initials: A
authors.lastname: Singh
authors.affiliation: Brain Tumour Research Centre, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Mylene P
authors.initials: MP
authors.lastname: Madiesse-Timchou
authors.affiliation: National Hospital for Neurology and Neurosurgery, London.
authors.forename: D G T
authors.initials: DG
authors.lastname: Thomas
authors.affiliation: Brain Tumour Research Centre, University of Wolverhampton, Wolverhampton, UK.
authors.forename: John L
authors.initials: JL
authors.lastname: Darling
authors.affiliation: Brain Tumour Research Centre, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Warr
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D000242:Cyclic AMP; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517272:PDE1C protein, human; D006152:Cyclic GMP
keywords: PDE1C signalling; Vinpocetine; cAMP; cGMP