15-Lipoxygenase-1 re-expression in colorectal cancer alters endothelial cell features through enhanced expression of TSP-1 and ICAM-1
Author
Tunçer, S.
Keşküş, A. G.
Çolakoğlu, M.
Çimen, I.
Yener, C.
Konu, Ö.
Banerjee, S.
Date
2017-11Source Title
Cellular Signalling
Print ISSN
0898-6568
Publisher
Elsevier
Volume
39
Pages
44 - 54
Language
English
Type
ArticleItem Usage Stats
234
views
views
285
downloads
downloads
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.
Keywords
15-LOX-1Angiogenesis
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