Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases
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Peter J. Webster1, Anna T. Littlejohns1, Hannah J. Gaunt1, Richard S. Young1, Baptiste Rode1, Judith E. Ritchie1, Lucy F. Stead1, Sally Harrison1, Alastair Droop1,5, Heather L. Martin2, Darren C. Tomlinson2, Adam J. Hyman1, Hollie L. Appleby1, Sally Boxall2, Alexander F. Bruns1, Jing Li1, Raj K. Prasad3, J. Peter A. Lodge3, Dermot A. Burke1,4 and David J. Beech1
1School of Medicine, University of Leeds, Leeds LS2 9JT, UK
2School of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
3Department of Hepatobiliary and Transplant Surgery, St. James’s University Hospital, Leeds LS9 7TF, UK
4Department of Colorectal Surgery, St. James’s University Hospital, Leeds LS9 7TF, UK
5MRC Medical Bioinformatics Centre, University of Leeds, Leeds LS2 9NL, UK
David J. Beech, email: D.J.Beech@leeds.ac.uk
Keywords: checkpoint kinase, angiogenesis, colorectal cancer, DNA damage, endothelial cell
Received: October 02, 2016 Accepted: January 09, 2017 Published: February 02, 2017
Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1. Western blotting confirmed that WEE1 protein was upregulated in CLMECs. Knockdown of WEE1 by targeted short interfering RNA or the WEE1 inhibitor AZD1775 suppressed proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA breaks due to nucleotide shortage which then led to caspase 3-dependent apoptosis. The implication for CLMEC tube formation was striking with AZD1775 inhibiting tube branch points by 83%. WEE1 inhibitors might therefore be a therapeutic option for CLM and could be considered more broadly as anti-angiogenic agents in cancer treatment.
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