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

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      Author
      Tunçer, S.
      Keşküş, A. G.
      Çolakoğlu, M.
      Çimen, I.
      Yener, C.
      Konu, Ö.
      Banerjee, S.
      Date
      2017-11
      Source Title
      Cellular Signalling
      Print ISSN
      0898-6568
      Publisher
      Elsevier
      Volume
      39
      Pages
      44 - 54
      Language
      English
      Type
      Article
      Item Usage Stats
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      285
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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.
      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
      Permalink
      http://hdl.handle.net/11693/37424
      Published Version (Please cite this version)
      https://doi.org/10.1016/j.cellsig.2017.07.022
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