Cyclic nucleotide phosphodiesterase-1C ( PDE1C ) drives cell proliferation, migration and invasion in glioblastoma multiforme cells in vitro
Authors
Rowther, Farjana B.Wei, Weinbin
Dawson, Timothy P.
Ashton, Katherine
Singh, Anushree
Madiesse-Timchou, Mylene P.
Thomas, D.G.T.
Darling, John L.
Warr, Tracy
Issue Date
2015-01-25
Metadata
Show full item recordAbstract
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.Citation
Cyclic nucleotide phosphodiesterase-1C ( PDE1C ) drives cell proliferation, migration and invasion in glioblastoma multiforme cells in vitro 2016, 55 (3):268 Molecular CarcinogenesisPublisher
WileyJournal
Molecular CarcinogenesisDOI
10.1002/mc.22276Additional Links
http://doi.wiley.com/10.1002/mc.22276Type
Journal articleLanguage
enISSN
08991987Sponsors
Brain Tumour Charity (formerly known as Brain Tumour UK), Colin Oliphant Charitable Trust and Bill O’Sullivan Memorial Fund.ae974a485f413a2113503eed53cd6c53
10.1002/mc.22276