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Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway

BACKGROUND: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15...

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Autores principales: Khophai, Sasikamon, Thanee, Malinee, Techasen, Anchalee, Namwat, Nisana, Klanrit, Poramate, Titapun, Attapol, Jarearnrat, Apiwat, Sa-Ngiamwibool, Prakasit, Loilome, Watcharin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198876/
https://www.ncbi.nlm.nih.gov/pubmed/30410359
http://dx.doi.org/10.2147/OTT.S178942
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author Khophai, Sasikamon
Thanee, Malinee
Techasen, Anchalee
Namwat, Nisana
Klanrit, Poramate
Titapun, Attapol
Jarearnrat, Apiwat
Sa-Ngiamwibool, Prakasit
Loilome, Watcharin
author_facet Khophai, Sasikamon
Thanee, Malinee
Techasen, Anchalee
Namwat, Nisana
Klanrit, Poramate
Titapun, Attapol
Jarearnrat, Apiwat
Sa-Ngiamwibool, Prakasit
Loilome, Watcharin
author_sort Khophai, Sasikamon
collection PubMed
description BACKGROUND: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development. PURPOSE: We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue. We also investigated the efficiency of zileuton (5-LOX inhibitor) treatment and BML-111 (LXA4 analog) addition on CCA cell lines properties. PATIENTS AND METHODS: The expression of 5-LOX and 15-LOX-1 in fifty human cholangiocarcinoma (CCA) tissue was analyzed using immunohistochemical staining. In addition, the effect of zileuton and BML-111 on CCA cell growth and migration was demonstrated using a cell viability assay and wound-healing assay, respectively. Furthermore, the molecular mechanism by which zileuton inhibits CCA cell migration was revealed using immunofluorescent staining and western blot analysis, respectively. RESULTS: We demonstrate that the upregulation of 5-LOX is significantly correlated with CCA recurrent status. A positive 15-LOX-1 signal was significantly associated with a longer survival time in CCA patients. We found that co-expression of 5-LOX and 15-LOX-1 resulted in a relatively good prognosis in CCA patients. In addition, zileuton could inhibit CCA cell migration as well as BML-111. Interestingly, zileuton treatment not only downregulated 5-LOX, but also upregulated 15-LOX-1, together with reversing the epithelial-mesenchymal transition to mesenchymal-epithelial transition phenotype as observed in EMT marker western blot. CONCLUSION: These findings suggest that 5-LOX and 15-LOX-1 play a key role in CCA and may serve as targets for CCA therapy.
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spelling pubmed-61988762018-11-08 Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway Khophai, Sasikamon Thanee, Malinee Techasen, Anchalee Namwat, Nisana Klanrit, Poramate Titapun, Attapol Jarearnrat, Apiwat Sa-Ngiamwibool, Prakasit Loilome, Watcharin Onco Targets Ther Original Research BACKGROUND: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development. PURPOSE: We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue. We also investigated the efficiency of zileuton (5-LOX inhibitor) treatment and BML-111 (LXA4 analog) addition on CCA cell lines properties. PATIENTS AND METHODS: The expression of 5-LOX and 15-LOX-1 in fifty human cholangiocarcinoma (CCA) tissue was analyzed using immunohistochemical staining. In addition, the effect of zileuton and BML-111 on CCA cell growth and migration was demonstrated using a cell viability assay and wound-healing assay, respectively. Furthermore, the molecular mechanism by which zileuton inhibits CCA cell migration was revealed using immunofluorescent staining and western blot analysis, respectively. RESULTS: We demonstrate that the upregulation of 5-LOX is significantly correlated with CCA recurrent status. A positive 15-LOX-1 signal was significantly associated with a longer survival time in CCA patients. We found that co-expression of 5-LOX and 15-LOX-1 resulted in a relatively good prognosis in CCA patients. In addition, zileuton could inhibit CCA cell migration as well as BML-111. Interestingly, zileuton treatment not only downregulated 5-LOX, but also upregulated 15-LOX-1, together with reversing the epithelial-mesenchymal transition to mesenchymal-epithelial transition phenotype as observed in EMT marker western blot. CONCLUSION: These findings suggest that 5-LOX and 15-LOX-1 play a key role in CCA and may serve as targets for CCA therapy. Dove Medical Press 2018-10-16 /pmc/articles/PMC6198876/ /pubmed/30410359 http://dx.doi.org/10.2147/OTT.S178942 Text en © 2018 Khophai et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Khophai, Sasikamon
Thanee, Malinee
Techasen, Anchalee
Namwat, Nisana
Klanrit, Poramate
Titapun, Attapol
Jarearnrat, Apiwat
Sa-Ngiamwibool, Prakasit
Loilome, Watcharin
Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway
title Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway
title_full Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway
title_fullStr Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway
title_full_unstemmed Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway
title_short Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway
title_sort zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the akt signaling pathway
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198876/
https://www.ncbi.nlm.nih.gov/pubmed/30410359
http://dx.doi.org/10.2147/OTT.S178942
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