15-Lipoxygenase-1 re-expression in colorectal cancer alters endothelial cell features through enhanced expression of TSP-1 and ICAM-1

Date
2017-11
Authors
Tunçer, S.
Keşküş, A. G.
Çolakoğlu, M.
Çimen, I.
Yener, C.
Konu, Ö.
Banerjee, S.
Advisor
Supervisor
Co-Advisor
Co-Supervisor
Instructor
Source Title
Cellular Signalling
Print ISSN
0898-6568
Electronic ISSN
Publisher
Elsevier
Volume
39
Issue
Pages
44 - 54
Language
English
Type
Article
Journal Title
Journal ISSN
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Abstract

15-lipoxygenase-1 (15-LOX-1) oxygenates linoleic acid to 13(S)-hydroxyoctadecadienoic acid (HODE). The enzyme is widely suppressed in different cancers and its re-expression has tumor suppressive effects. 15-LOX-1 has been shown to inhibit neoangiogenesis in colorectal cancer (CRC); in the present study we confirm this phenomenon and describe the mechanistic basis. We show that re-expression of 15-LOX-1 in CRC cell lines resulted in decreased transcriptional activity of HIF1α and reduced the expression and secretion of VEGF in both normoxic and hypoxic conditions. Conditioned medium (CM) was obtained from CRC or prostate cancer cell lines re-expressing 15-LOX-1 (15-LOX-1CM). 15-LOX-1CM treated aortic rings from 6-week old C57BL/6 mice showed significantly less vessel sprouting and more organized structure of vascular network. Human umbilical vein endothelial cells (HUVECs) incubated with 15-LOX-1CM showed reduced motility, enhanced expression of intercellular cell adhesion molecule (ICAM-1) and reduced tube formation but no change in proliferation or cell-cycle distribution. HUVECs incubated with 13(S)-HODE partially phenocopied the effects of 15-LOX-1CM, i.e., showed reduced motility and enhanced expression of ICAM-1, but did not reduce tube formation, implying the importance of additional factors. Therefore, a Proteome Profiler Angiogenesis Array was carried out, which showed that Thrombospondin-1 (TSP-1), a matrix glycoprotein known to strongly inhibit neovascularization, was expressed significantly more in HUVECs incubated with 15-LOX-1CM. TSP-1 blockage in HUVECs reduced the expression of ICAM-1 and enhanced cell motility, thereby providing a mechanism for reduced angiogenesis. The anti-angiogenic effects of 15-LOX-1 through enhanced expressions of ICAM-1 and TSP-1 are novel findings and should be explored further to develop therapeutic options.

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Keywords
15-LOX-1, Angiogenesis, Colorectal cancer, ICAM-1, Thrombospondin-1, 13 hydroxyoctadecadienoic acid, 15 lipoxygenase 1, Arachidonate 15 lipoxygenase, Hypoxia inducible factor 1alpha, Intercellular adhesion molecule 1, Polyunsaturated fatty acid, Thrombospondin 1, Unclassified drug, Animal tissue, Aortic ring (slice), Article, Cell cycle, Cell motility, Cell proliferation, Colorectal cancer, Controlled study, Ex vivo study, Human, Human cell, LNCaP cell line, Male, Mouse, Nonhuman, Priority journal, Prostate cancer cell line, Protein expression, Signal transduction, Transcription regulation, Tumor vascularization, Umbilical vein endothelial cell
Citation
Published Version (Please cite this version)