Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms

J. Woolard; W. Vousden; S. J. Moss; A. Krishnakumar; M. V. R. Gammons; D. G. Nowak; N. Dixon; J. Micklefield; A. Spannhoff; M. T. Bedford; M. A. Gregory; C. J. Martin; P. F. Leadlay; M. Q. Zhang; S. J. Harper; D. O. Bates; B. Wilkinson

doi:10.1039/C0SC00297F

Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms†

J. Woolard,^b W. Vousden,^a S. J. Moss,^a A. Krishnakumar,^b M. V. R. Gammons,^b D. G. Nowak,^b N. Dixon,^d J. Micklefield,^d A. Spannhoff,^e M. T. Bedford,^e M. A. Gregory,^a C. J. Martin,^a P. F. Leadlay,^c M. Q. Zhang,^a S. J. Harper,^b D. O. Bates*^b and B. Wilkinson*^a

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^a Biotica, Chesterford Research Park, Cambridge, UK
E-mail: barrie.wilkinson@biotica.com
Fax: +44 (0)1799 532921
Tel: +44 (0)1799 532925

^b Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, School of Veterinary Sciences, University of Bristol, Southwell Street Bristol, UK
E-mail: dave.bates@bristol.ac.uk
Fax: +44 (0)117 9288151
Tel: +44 (0)117 9289818

^c Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, UK

^d School of Chemistry and Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, UK

^e The University of Texas M.D. Anderson Cancer Centre, Science Park-Research Division, Smithville, Texas, USA

Abstract

The polyketide natural product borrelidin 1 is a potent inhibitor of angiogenesis and spontaneous metastasis. Affinity biopanning of a phage display library of colon tumour cell cDNAs identified the tandem WW domains of spliceosome-associated protein formin binding protein 21 (FBP21) as a novel molecular target of borrelidin, suggesting that borrelidin may act as a modulator of alternative splicing. In support of this idea, 1, and its more selective analog 2, bound to purified recombinant WW domains of FBP21. They also altered the ratio of vascular endothelial growth factor (VEGF) isoforms in retinal pigmented endothelial (RPE) cells in favour of anti-angiogenic isoforms. Transfection of RPE cells with FBP21 altered the ratio in favour of pro-angiogenic VEGF isoforms, an effect inhibited by 2. These data implicate FBP21 in the regulation of alternative splicing and suggest the potential of borrelidin analogs as tools to deconvolute key steps of spliceosome function.

Chemical Science

Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms†

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Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms

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