Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands

Ray, Denise M.; Bernstein, Steven H.; Phipps, Richard P.

doi:10.1016/j.clim.2004.06.011

Cited by 51 publications

(46 citation statements)

References 36 publications

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“…Human B lymphocytes abundantly express PPAR␥ and are killed by a variety of structurally dissimilar small molecule PPAR␥ agonists (12,41). According to our previous studies and the data reported herein, the EC 50 for cell death induction by PPAR␥ agonists in human B lymphocytes is 2 M for 15d-PGJ 2 and 7 M for ciglitazone (12).…”

Section: A Dn Ppar␥ Does Not Prevent Ppar␥ Agonist-induced Cell Deathmentioning

confidence: 83%

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The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

Ray

Akbıyık

Phipps

2006

The Journal of Immunology

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Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARγ ligands, including the endogenous ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARγ for apoptosis induction is unknown. In this study, we used a PPARγ dominant-negative approach and a small molecule irreversible PPARγ antagonist and found that these inhibitors prevented PPARγ activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARγ agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARγ but did not kill B lymphocytes, further supporting a non-PPARγ-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ2 and ciglitazone on reactive oxygen species were investigated. 15d-PGJ2, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ2 structure in the apoptosis mechanism. In addition, 15d-PGJ2 caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ2, but not by ciglitazone. These findings indicate that the expression of PPARγ may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARγ agonists. Furthermore, these new findings support continued investigation into the use of PPARγ agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.

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Section: A Dn Ppar␥ Does Not Prevent Ppar␥ Agonist-induced Cell Deathmentioning

confidence: 83%

“…We previously reported that both mouse and human normal and malignant B lymphocytes abundantly express PPAR␥ and undergo apoptosis after exposure to both natural and synthetic PPAR␥ agonists (11,12,41). However, it is not known if PPAR␥ is required for apoptosis induction of human B lymphocytes.…”

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confidence: 99%

The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

Ray

Akbıyık

Phipps

2006

The Journal of Immunology

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“…We have recently shown that 15-deoxy-D12,14-prostaglandin J 2 (15d-PGJ 2 ), an oxidized lipid with an a/h unsaturated ketone moiety that is similar in character to CDDO, elicits apoptosis of both normal and malignant B cells (28)(29)(30)(31). In addition, we have shown (32) that CDDO elicits apoptosis of human diffuse large B-cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid and Its Derivatives Elicit Human Lymphoid Cell Apoptosis through a Novel Pathway Involving the Unregulated Mitochondrial Permeability Transition Pore

Brookes¹,

Morse²,

Ray³

et al. 2007

Cancer Research

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2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its C 28 imidazole and dinitrile derivatives are novel oleanane triterpenoids exhibiting promise as both therapeutic and preventative agents for cancer. Herein we show that these triterpenoids induce normal and malignant B-lymphoid cell apoptosis, with the C 28 derivatives being more potent than CDDO, through a novel mitochondrial mechanism. We show using both normal and malignant human B cells, as well as isolated rat mitochondria, that CDDO directly interacts with a limited number of as yet undefined mitochondrial proteins. Such an interaction results in the loss of mitochondrial thiol status and the secondary modification of numerous mitochondrial protein thiols. Our data further suggest that such modifications result in the formation of high molecular weight protein aggregates that form ''unregulated,'' constitutively open, cyclosporin A-insensitive permeability transition (PT) pores. The formation of such PT pores results in the subsequent generation of mitochondrial superoxide and cell death. In total, our studies (a) suggest a novel mechanism of action for triterpenoid-induced cell death; (b) are among the first to directly support the existence of an unregulated PT pore formed by mitochondrial protein aggregates, as first proposed by Lemasters and colleagues; and (c) validate such an unregulated PT pore as a viable target for the development of new cancer therapeutics. [Cancer Res 2007;67(4):1793-802]

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“…PPARg regulates the expression of COX-2, and prostaglandin 15d-PGJ 2 is a natural ligand for the PPARg that induces apoptosis in myeloma cell lines. 3 During the last decade, new treatments with immunomodulatory drugs and proteosome inhibitors have been introduced and have led to improved survival of the patients. These drugs induce apoptosis of myeloma cells, interrupt the interaction between myeloma cells and stromal cells in the BM, inhibit angiogenesis and inhibit the secretion of IL-1b and IL-6.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Another nuclear activation factor involved in the inflammatory response has been found in B-cell lymphomas and multiple myeloma (MM) cells. 3 The nuclear receptor, peroxisome proliferator-activated receptor-g (PPARg), is an important transcription factor and member of the nuclear hormone receptor superfamily. PPARg regulates the expression of COX-2, and prostaglandin 15d-PGJ 2 is a natural ligand for the PPARg that induces apoptosis in myeloma cell lines.…”

Section: Introductionmentioning

confidence: 99%

The polymorphism IL-1β T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT

Vangsted

Klausen

Ruminski

et al. 2008

Bone Marrow Transplant

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Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). Therefore, it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients. We investigated 348 MM patients undergoing high-dose melphalan treatment followed by Auto-SCT and examined the influence of single nucleotide polymorphisms (SNPs) in genes involved in the inflammatory response. We found that the polymorphism IL-1b T-31C significantly influenced overall survival (OS; P ¼ 0.02) and that carriers of the variant C-allele had a significantly longer survival than homozygous wild-type allele TT-carriers (relative risk 0.6 (95% CI ¼ 0.5-0.9); P ¼ 0.008). The polymorphisms IL-6 G-174C, IL-10 C592A, PPARc2 Pro 12 Ala, COX-2 A-1195G, COX-2 T8473C and NFKB1 ins/del did not influence the OS in this group of patients. Furthermore, homozygous carriers of the variant allele of IL-1b T-31C were at 1.37-fold (CI ¼ 1.05-1.80) increased risk of MM as compared with population-based controls (P ¼ 0.02). Our results indicate that IL-1b is involved in the pathogenesis of MM.

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Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands

Cited by 51 publications

References 36 publications

The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid and Its Derivatives Elicit Human Lymphoid Cell Apoptosis through a Novel Pathway Involving the Unregulated Mitochondrial Permeability Transition Pore

The polymorphism IL-1β T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT

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