Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.

Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA) release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell surv...

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Autores principales:	Emma Bell, Frida Ponthan, Claire Whitworth, Frank Westermann, Huw Thomas, Christopher P F Redfern
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7e84869a36204216bea34ec69dd4918e
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spelling	oai:doaj.org-article:7e84869a36204216bea34ec69dd4918e2021-11-18T07:38:05ZCell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.1932-620310.1371/journal.pone.0068859https://doaj.org/article/7e84869a36204216bea34ec69dd4918e2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874790/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA) release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell survival signalling. To test this, we inhibited phospholipase A2-mediated AA release, cyclooxygenases and lipoxygenases with small-molecule inhibitors to determine if this would sensitise cells to cell death after RA treatment. The data suggest that, in response to RA, phospholipase A2-mediated release of AA and subsequent metabolism by lipoxygenases is important for cell survival. Evidence from gene expression reporter assays and PPARδ knockdown suggests that lipoxygenase metabolites activate PPARδ. The involvement of PPARδ in cell survival is supported by results of experiments with the PPARδ inhibitor GSK0660 and siRNA-mediated knockdown. Quantitative reverse transcriptase PCR studies demonstrated that inhibition of 5-lipoxygenase after RA treatment resulted in a strong up-regulation of mRNA for PPARδ2, a putative inhibitory PPARδ isoform. Over-expression of PPARδ2 using a tetracycline-inducible system in neuroblastoma cells reduced proliferation and induced cell death. These data provide evidence linking lipoxygenases and PPARδ in a cell survival-signalling mechanism and suggest new drug-development targets for malignant and hyper-proliferative diseases.Emma BellFrida PonthanClaire WhitworthFrank WestermannHuw ThomasChristopher P F RedfernPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e68859 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emma Bell Frida Ponthan Claire Whitworth Frank Westermann Huw Thomas Christopher P F Redfern Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.
description	Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA) release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell survival signalling. To test this, we inhibited phospholipase A2-mediated AA release, cyclooxygenases and lipoxygenases with small-molecule inhibitors to determine if this would sensitise cells to cell death after RA treatment. The data suggest that, in response to RA, phospholipase A2-mediated release of AA and subsequent metabolism by lipoxygenases is important for cell survival. Evidence from gene expression reporter assays and PPARδ knockdown suggests that lipoxygenase metabolites activate PPARδ. The involvement of PPARδ in cell survival is supported by results of experiments with the PPARδ inhibitor GSK0660 and siRNA-mediated knockdown. Quantitative reverse transcriptase PCR studies demonstrated that inhibition of 5-lipoxygenase after RA treatment resulted in a strong up-regulation of mRNA for PPARδ2, a putative inhibitory PPARδ isoform. Over-expression of PPARδ2 using a tetracycline-inducible system in neuroblastoma cells reduced proliferation and induced cell death. These data provide evidence linking lipoxygenases and PPARδ in a cell survival-signalling mechanism and suggest new drug-development targets for malignant and hyper-proliferative diseases.
format	article
author	Emma Bell Frida Ponthan Claire Whitworth Frank Westermann Huw Thomas Christopher P F Redfern
author_facet	Emma Bell Frida Ponthan Claire Whitworth Frank Westermann Huw Thomas Christopher P F Redfern
author_sort	Emma Bell
title	Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.
title_short	Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.
title_full	Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.
title_fullStr	Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.
title_full_unstemmed	Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.
title_sort	cell survival signalling through pparδ and arachidonic acid metabolites in neuroblastoma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/7e84869a36204216bea34ec69dd4918e
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Cell survival signalling through PPARδ and arachidonic acid metabolites in neuroblastoma.

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