Ciglitizone and 15d PGJ2 induce apoptosis in Jurkat and Raji cells

Kanunfre, Carla Cristine; Freitas, Jofre Jacob da Silva; Pompéia, Celine; Almeida, Débora Cristina Gonçalves de; Cury-Boaventura, Maria Fernanda; Verlengia, Rozângela; Curi, Rui

doi:10.1016/j.intimp.2004.05.007

Cited by 18 publications

(19 citation statements)

References 44 publications

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“…Ciglitazone elicited fast induction of cell death, which is in line with previous publications (Atarod and Kehrer, 2004;Kanunfre et al, 2004). Rosiglitazone did not alter cell viability at any concentration after 4 h, which is in agreement with data from hepatoma cells (Narayanan et al, 2003).…”

Section: Discussionsupporting

confidence: 92%

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Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

Soller

Dröse²,

Brandt³

et al. 2007

Mol Pharmacol

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Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPAR␥-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPAR␥-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese (III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone-and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.

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Section: Discussionsupporting

confidence: 92%

“…PPAR␥ activation by TZDs provoked T-cell apoptosis (Harris and Phipps, 2000Tautenhahn et al, 2003;Kanunfre et al, 2004). However, TZDs also activate cell death pathways independent of PPAR␥.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

Soller

Dröse²,

Brandt³

et al. 2007

Mol Pharmacol

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“…It is noteworthy that for Western blotting the nuclear fraction was loaded at a much higher concentration (approximately 20 times more protein) than the cytosolic fraction. Although PPAR␥ has been reported as being predominantly localized to the nucleus, there is an earlier report describing PPAR␥ in Jurkat cells as being predominantly a cytosolic protein (Kanunfre et al, 2004). In addition to receptor activation, PPAR␥ ligands led to receptor ubiquitination (Hauser et al, 2000).…”

Section: D-pgj2-g a Putative Metabolite Of 2-ag Modulates Nfat 821mentioning

confidence: 97%

“…PPAR␥ is a ligand-activated transcription factor that is predominantly localized to the nucleus, although cytosolic localization has also been reported (Kanunfre et al, 2004;von Knethen et al, 2007). PPAR␥ usually exists as a heterodimer with retinoid X receptor (RXR).…”

Section: Introductionmentioning

confidence: 99%

15-Deoxy-Δ^12,14-Prostaglandin J₂-Glycerol, a Putative Metabolite of 2-Arachidonyl Glycerol and a Peroxisome Proliferator-Activated Receptor γ Ligand, Modulates Nuclear Factor of Activated T Cells

Raman

Kaplan

Kaminski

2012

J Pharmacol Exp Ther

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2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative released on demand from membrane precursors. 2-AG-mediated suppression of interleukin (IL)-2 depends on cyclooxygenase 2 (COX-2) metabolism and peroxisome proliferator-activated receptor ␥ (PPAR␥) activation. 15-Deoxy-⌬ 12,14 -prostaglandin J 2 -glycerol ester (15d-PGJ 2 -G), a putative COX-2 metabolite of 2-AG, acts as a PPAR␥ ligand and produces IL-2 suppression in activated Jurkat T cells, in part, by decreasing nuclear factor of activated T cells (NFAT) transcriptional activity. The objective of the present studies was to investigate the mechanism by which 15d-PGJ 2 -G modulates NFAT activity to suppress IL-2. 15d-PGJ 2 -G treatment decreased phorbol 12-myristate 13-acetate (PMA)/calcium ionophore (I o )-induced NFAT DNA binding to the human IL-2 promoter and nuclear NFAT2 accumulation. It is noteworthy that 15d-PGJ 2 -G treatment increased active nuclear HDM2 (human homolog of the oncoprotein and E3 ubiquitin ligase murine double minute 2) expression, whereas there was no change in the expression of glycogen synthase kinase 3␤, both of which regulate NFAT. 15d-PGJ 2 -G and other PPAR␥ agonists, such as rosiglitazone and ciglitazone, decreased PMA/I o -mediated elevation in intracellular calcium concentration ([Ca 2ϩ ] i ) in activated Jurkat cells. We were surprised to find that the PPAR␥ antagonists 2-chloro-5-nitro-N-4-pyridinylbenzamide (T0070907) and 2-chloro-5-nitrobenzanilide (GW9662) also decreased the PMA/I o -mediated elevation in [Ca 2ϩ ] i in activated T cells. In addition, the presence of T0070907 plus 15d-PGJ 2 -G produced an additive decrease in PMA/I o -mediated elevation of [Ca 2ϩ ] i , suggesting that the 15d-PGJ 2 -G effects on calcium might be either PPAR␥-independent or -dependent on occupation of the PPAR␥ ligand binding domain. Collectively, our findings suggest that 15d-PGJ 2 -G increases active nuclear HDM2, which could lead to a decrease in NFAT2 and IL-2 suppression.

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“…In addition other studies also confirmed the anti-apoptotic role of TERT in apoptosis induced by other stimuli such as 15-deoxy-Δ 12, 14 -prostaglandin J2 (15d-PGJ2) which kills cells through induction of ROS production (Kanunfre et al, 2004;Shin et al, 2009). Interestingly it was observed that 15d-PGJ2 treatment induces TERT downregulation which seems to be an important feature of 15d-PGJ2-mediated cell death and may outline the antiapoptotic function of TERT (Moriai et al, 2009).…”

Section: Relationships Between Tert and Apoptotic Pathwaysmentioning

confidence: 74%

Extra-Telomeric Effects of Telomerase (hTERT) in Cell Death

Bellot¹

2013

Apoptosis

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Ciglitizone and 15d PGJ2 induce apoptosis in Jurkat and Raji cells

Cited by 18 publications

References 44 publications

Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

15-Deoxy-Δ^12,14-Prostaglandin J₂-Glycerol, a Putative Metabolite of 2-Arachidonyl Glycerol and a Peroxisome Proliferator-Activated Receptor γ Ligand, Modulates Nuclear Factor of Activated T Cells

Extra-Telomeric Effects of Telomerase (hTERT) in Cell Death

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Ciglitizone and 15d PGJ2 induce apoptosis in Jurkat and Raji cells

Cited by 18 publications

References 44 publications

Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

15-Deoxy-Δ12,14-Prostaglandin J2-Glycerol, a Putative Metabolite of 2-Arachidonyl Glycerol and a Peroxisome Proliferator-Activated Receptor γ Ligand, Modulates Nuclear Factor of Activated T Cells

Extra-Telomeric Effects of Telomerase (hTERT) in Cell Death

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Product

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About

15-Deoxy-Δ^12,14-Prostaglandin J₂-Glycerol, a Putative Metabolite of 2-Arachidonyl Glycerol and a Peroxisome Proliferator-Activated Receptor γ Ligand, Modulates Nuclear Factor of Activated T Cells