Activation of Peroxisome Proliferator-Activated Receptor γ Contributes to the Survival of T Lymphoma Cells by Affecting Cellular Metabolism

Yang, Chunyan; Jo, Seung Hee; Csernus, Balázs; Hyjek, Elizabeth; Liu, Yifang; Chadburn, Amy; Wang, Y. Lynn

doi:10.2353/ajpath.2007.060651

Cited by 29 publications

(36 citation statements)

References 43 publications

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“…36 PPAR␥, a ligand-activated transcription factor belonging to the nuclear receptor superfamily, regulates gene expression of key proteins involved in lipid metabolism, vascular inflammation, and proliferation, providing protection against atherosclerosis and coronary events. 37 Recently, Yang et al 38 have demonstrated that PPAR␥ activation lowers the ROS levels through coordinated transcriptional control of a set of proteins and enzymes involved in ROS metabolism. PPAR␥ increases the amount of uncoupling protein 2 and superoxide dismutase and reduces the amount of the p67 subunit of NADPH oxidase at both the mRNA and protein levels in T lymphoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System

et al. 2008

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Abstract-Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT 1 R), activates peroxisome proliferator activated receptor ␥ (PPAR␥) signaling that interferes with nitric oxide (NO) system. Because aging of endothelial cells (ECs) is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-system through blocking AT 1 R and activating PPAR␥ signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPAR␥ antagonist) until the twelfth passage. During the process of aging, PPAR␥ protein expression decreased significantly, whereas the expression of AT 1 R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F 2␣ formation. This effect was associated with an upregulated activity and protein expression of DDAH, accompanied by a decrease in ADMA concentration, an increase in NO metabolites, and delayed senescence. Blockade of PPAR␥ signaling by GW9662 or PPAR␥ small-interference RNA prevented the effect of telmisartan on ADMA-DDAH-NO system. Coincubation with Ang II did not affect the effect of telmisartan-delayed senescence, whereas Ang II itself accelerated endothelial aging. Moreover, AT 1 R blocker eprosartan that did not influence PPAR␥ protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPAR␥ signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan translationally and posttranslationally upregulated DDAH expression via activation of PPAR␥ signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence. Key Words: telmisartan Ⅲ angiotensin II type 1 receptor Ⅲ peroxisome proliferator activated receptor ␥ Ⅲ oxidative stress Ⅲ asymmetrical dimethylarginine Ⅲ nitric oxide Ⅲ aging A ging is a well-documented risk factor for cardiovascular diseases. One of the possible physiopathological mechanisms through which increasing age may lead to cardiovascular damage is the promotion of endothelial dysfunction. 1 Aged human endothelial cells (ECs), which produce less NO, more asymmetrical dimethylarginine (ADMA), a novel cardiovascular risk factor, and more reactive oxygen species (ROS), 2-5 could account for endothelial dysfunction and development of cardiovascular diseases. 6 -10 We and other have previously demonstrated that aging of human ECs can be altered by several different factors contributing to delay or accelerate the process of aging. [2][3][4][5]11,12 These results suggest that the process of endothelial aging may be an influenceable process and raise the possibility of therapies for preventing various cardiovascular diseases in the elderly.Telmisartan, a highly lipophilic angiotensin (Ang) II type 1 receptor (AT 1 R) blocker (ARB), is used for the treatme...

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Section: Discussionmentioning

confidence: 99%

Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System

et al. 2008

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“…For analysis of cell viability, cells were stained with 2 μg/mL propidium iodide (Molecular Probe), as described previously (21,22). Ten thousand events in a live cell gate were counted by a FACS Calibur (BD Biosciences).…”

Section: Translational Relevancementioning

confidence: 99%

“…Intracellular reactive oxygen species were detected with 5-(and 6-)carboxy-2′,7′-dichlorodihydrofluorescein diacetate (DCF; Molecular Probes), as described previously (21,22). Aliquots of 3 × 10 5 cells were resuspended in 500 μL of RPMI 1640 containing 5% FBS and loaded with 10 μmol/L DCF for 30 min at 37°C.…”

Section: Translational Relevancementioning

confidence: 99%

“…Analyses were conducted as described previously (22). The following antibodies were used to probe the corresponding proteins: anti-phospho-SRC (Y416), anti-SRC, anti-β-actin (Cell Signaling), anti-phospho-LYN (Y396; Epitomics), anti-LYN, antiphospho-HCK (Y411), anti-HCK, anti-BCL2 (Santa Cruz Biotechnology), and anti-X-linked inhibitor of apoptosis (XIAP; BD).…”

Section: Translational Relevancementioning

confidence: 99%

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Activities of SYK and PLCγ2 Predict Apoptotic Response of CLL Cells to SRC Tyrosine Kinase Inhibitor Dasatinib

Song

Lü

Furman

et al. 2010

Clinical Cancer Research

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Purpose: B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL.Experimental Design: Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors.Results: Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cγ2, correlate well with the apoptotic response of CLL cells to dasatinib.Conclusions: Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cγ2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment. Clin Cancer Res; 16(2); 587-99. ©2010 AACR.

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“…For instance, rosiglitazone was found to protect lymphoma cells from serum starvation-induced apoptosis. 22 A low dose of rosiglitazone was found to stimulate the growth of estrogen receptor-positive breast cancer cells, whereas a high dose of rosiglitazone inhibits their proliferation. 23 Furthermore, the effect of rosiglitazone on cancer cells can be either PPARg-dependent or independent, despite it being a potent and highly selective agonist for PPARg.…”

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confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP 2/2 cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.

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Activation of Peroxisome Proliferator-Activated Receptor γ Contributes to the Survival of T Lymphoma Cells by Affecting Cellular Metabolism

Cited by 29 publications

References 43 publications

Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System

Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System

Activities of SYK and PLCγ2 Predict Apoptotic Response of CLL Cells to SRC Tyrosine Kinase Inhibitor Dasatinib

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

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