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A Ligand of Peroxisome-Proliferator-Activated Receptor y (PPARy) has potential in the treatment of neuroblastoma

A Ligand of Peroxisome-Proliferator-Activated Receptor y (PPARy) has potential in the treatment of neuroblastoma
A Ligand of Peroxisome-Proliferator-Activated Receptor y (PPARy) has potential in the treatment of neuroblastoma

There are three isoforms of PPARs, α, β and γ and activation of PPARγ has been shown to inhibit the growth of many cancer cell types. PPARs, α, β, and γ are activated by fatty acids and PPARγ is also activated by the fatty acid metabolite, 15-deoxyΔ12,14-prostaglandin J2 (15dPGJ2). Fatty acids marginally inhibited IMR-32 cell growth and altered the membrane phospholipids of the cells. Fatty acids activated PPAR-induced transcription, but this did not relate to their cellular effects as docosahexaenoic acid, which had the greatest effect on the cells, activated PPARs the least. 15dPGJ2 inhibited the growth of IMR-32 and Kelly cell lines, but was more effective than fatty acids. 15dPGJ2 induced IMR-32 cells to arrest at G2/M phase of the cell cycle, coinciding with nuclear translocation of p53 and down-regulation of PAX3. Subsequently, the cells died by a process, which required de novo protein synthesis, but did not exhibit features of classical apoptosis. IMR-32 cells treated with 15dPGJ2 underwent autophagic cell death. This involved the formation of autophagic vesicles, which target cellular components such as mitochondria for destruction and resulted in cell death. Decoy oligonucleotides to PPARs prevented 15dPGJ2 from inhibiting IMR-32 cell growth and showed that 15dPGJ2 acts specifically through PPARs. Sphingosine-1-phosphate (SIP) can be removed from foetal calf serum by delipidation. Culturing IMR-32 cells under delipidated conditions altered the cellular effects of PPAR ligands. Both 15dPGJ2 and fatty acids effectively inhibited the growth of IMR-32 cells and induced apoptosis. SIP activates mitogen-activated protein kinases (MAPKs), which can down-regulate PPARγ activity. Therefore under delipidated conditions, a higher level of activation of PPARγ may result in IMR-32 cells undergoing apoptosis instead of autophagy. This suggests that PPARγ ligands such as 15pPGJ2 have therapeutic potential in the treatment of cancers including neuroblastoma. PPARγ ligands may also be more effective in combination with inhibitors of MAPKs or S1P, as removal of S1P from the culture medium affects the response of neuroblastoma cells to PPARγ ligands.

University of Southampton
Rodway, Helen Anne
f15633a3-9704-4366-ac93-8f62cdee4df7
Rodway, Helen Anne
f15633a3-9704-4366-ac93-8f62cdee4df7

Rodway, Helen Anne (2002) A Ligand of Peroxisome-Proliferator-Activated Receptor y (PPARy) has potential in the treatment of neuroblastoma. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

There are three isoforms of PPARs, α, β and γ and activation of PPARγ has been shown to inhibit the growth of many cancer cell types. PPARs, α, β, and γ are activated by fatty acids and PPARγ is also activated by the fatty acid metabolite, 15-deoxyΔ12,14-prostaglandin J2 (15dPGJ2). Fatty acids marginally inhibited IMR-32 cell growth and altered the membrane phospholipids of the cells. Fatty acids activated PPAR-induced transcription, but this did not relate to their cellular effects as docosahexaenoic acid, which had the greatest effect on the cells, activated PPARs the least. 15dPGJ2 inhibited the growth of IMR-32 and Kelly cell lines, but was more effective than fatty acids. 15dPGJ2 induced IMR-32 cells to arrest at G2/M phase of the cell cycle, coinciding with nuclear translocation of p53 and down-regulation of PAX3. Subsequently, the cells died by a process, which required de novo protein synthesis, but did not exhibit features of classical apoptosis. IMR-32 cells treated with 15dPGJ2 underwent autophagic cell death. This involved the formation of autophagic vesicles, which target cellular components such as mitochondria for destruction and resulted in cell death. Decoy oligonucleotides to PPARs prevented 15dPGJ2 from inhibiting IMR-32 cell growth and showed that 15dPGJ2 acts specifically through PPARs. Sphingosine-1-phosphate (SIP) can be removed from foetal calf serum by delipidation. Culturing IMR-32 cells under delipidated conditions altered the cellular effects of PPAR ligands. Both 15dPGJ2 and fatty acids effectively inhibited the growth of IMR-32 cells and induced apoptosis. SIP activates mitogen-activated protein kinases (MAPKs), which can down-regulate PPARγ activity. Therefore under delipidated conditions, a higher level of activation of PPARγ may result in IMR-32 cells undergoing apoptosis instead of autophagy. This suggests that PPARγ ligands such as 15pPGJ2 have therapeutic potential in the treatment of cancers including neuroblastoma. PPARγ ligands may also be more effective in combination with inhibitors of MAPKs or S1P, as removal of S1P from the culture medium affects the response of neuroblastoma cells to PPARγ ligands.

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Published date: 2002

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Local EPrints ID: 467163
URI: http://eprints.soton.ac.uk/id/eprint/467163
PURE UUID: 9cb0f689-85b2-4a88-a019-1332826468d4

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Date deposited: 05 Jul 2022 08:14
Last modified: 23 Jul 2022 01:17

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Author: Helen Anne Rodway

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