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Structurally diverse peroxisome proliferator-activated receptor agonists induce apoptosis in human uro-epithelial cells by a receptor-independent mechanism involving store-operated calcium channels

Chopra, B., Georgopoulos, Nikolaos T., Nicholl, A., Hinley, J., Oleksiewicz, M. B. and Southgate, J. (2009) Structurally diverse peroxisome proliferator-activated receptor agonists induce apoptosis in human uro-epithelial cells by a receptor-independent mechanism involving store-operated calcium channels. Cell Proliferation, 42 (5). pp. 688-700. ISSN 0960-7722

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Abstract

Objectives: Peroxisome proliferator-activated receptors (PPARs) are implicated in epithelial cell proliferation and differentiation, but investigation has been confounded by potential off-target effects of some synthetic PPAR ligands. Our aim was to determine mechanisms underlying the pro-apoptotic effect of synthetic PPAR agonists in normal human bladder uro-epithelial (urothelial) cells and to reconcile this with the role of PPARs in urothelial cytodifferentiation.

Materials and methods: Normal human urothelial (NHU) cells were grown as non-immortal lines in vitro and exposed to structurally diverse agonists ciglitazone, troglitazone, rosiglitazone (PPARγ), ragaglitazar (PPARα/γ), fenofibrate (PPARα) and L165041 (PPARβ/δ).

Results: NHU cells underwent apoptosis following acute exposure to ciglitazone, troglitazone or ragaglitazar, but not fenofibrate, L165041 or rosiglitazone, and this was independent of ERK or p38 MAP-kinase activation. Pro-apoptotic agonists induced sustained increases in intracellular calcium, whereas removal of extracellular calcium altered the kinetics of ciglitazone-mediated calcium release from sustained to transient. Cell death was accompanied by plasma-membrane disruption, loss of mitochondrial membrane-potential and caspase-9/caspase-3 activation. PPARγ-mediated apoptosis was unaffected following pre-treatment with PPARγ antagonist T0070907 and was strongly attenuated by store-operated calcium channel (SOC) inhibitors 2-APB and SKF-96365.

Conclusions: Our results provide a mechanistic basis for the ability of some PPAR agonists to induce death in NHU cells and demonstrate that apoptosis is mediated via PPAR-independent mechanisms, involving intracellular calcium changes, activation of SOCs and induction of the mitochondrial apoptotic pathway.

Item Type: Article
Subjects: Q Science > QH Natural history > QH301 Biology
Schools: School of Applied Sciences
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Depositing User: Cherry Edmunds
Date Deposited: 01 Dec 2009 14:07
Last Modified: 01 Dec 2009 14:07
URI: http://eprints.hud.ac.uk/id/eprint/6447

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