Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-γ in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-κB

Bren‐Mattison, Yvette; Meyer, Amy M.; Putten, Vicki Van; Li, Howard; Kuhn, Katherine; Stearman, Robert S.; Weiser‐Evans, Mary C.M.; Winn, Robert A.; Heasley, Lynn E.; Nemenoff, Raphael A.

doi:10.1124/mol.107.042002

Cited by 60 publications

(62 citation statements)

References 36 publications

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“…Also, ciglitazone suppressed COX-2 mRNA expression and COX-2 promoter activity, while upregulating peroxisome proliferator response element promoter activity in NSCLC cells further suggesting a negative modulator role for PPARγ ligands on the COX-2/PGE2 pathway in NSCLC [63] . Of note, in vitro studies and xenograft models have demonstrated that elevated COX-2 expression is critical for promoting lung tumorigenesis, and that the anti-tumorigenic effects of PPARγ ligands are mediated through suppression of COX-2 via increased activity of PTEN, decreased levels of phospho-Akt, and inhibition of nuclear factor-kB (NF-kB) activity [64] .…”

Section: Pparγ Ligands and Cyclooxygenase-2-related Pathwaysmentioning

confidence: 99%

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Han

Roman²

2010

WJBC

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Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily. Of the three PPARs identified to date (PPARγ, PPARβ/δ, and PPARα), PPARγ has been studied the most, in part because of the availability of PPARγ agonists (also known as PPARγ ligands) and its significant effects on the management of several human diseases including type 2 diabetes, metabolic syndrome, cardiovascular disease and cancers. PPARγ is expressed in many tumors including lung cancer, and its function has been linked to the process of lung cancer development, progression and metastasis. Studies performed in gynogenic and xenograft models of lung cancer showed decreased tumor growth and metastasis in animals treated with PPARγ ligands. Furthermore, data are emerging from retrospective clinical studies that suggest a protective role for PPARγ ligands on the incidence of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms and potential therapeutic effects of PPARγ ligands as a novel anti-lung cancer treatment strategy.

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Section: Pparγ Ligands and Cyclooxygenase-2-related Pathwaysmentioning

confidence: 99%

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Han

Roman²

2010

WJBC

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“…NF-kB activation was determined as previously described 43 with modifications. Briefly, HK-2 cells were grown to 50% confluence in six-well plates and transiently transfected with a NF-kB luciferase reporter cassette and a b-galactosidase reporter (used for normalizing the transfection efficiency).…”

Section: Nf-kb Activity Assay In Cultured Cellsmentioning

confidence: 99%

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Lanaspa

Ishimoto

Cicerchi

et al. 2014

Journal of the American Society of Nephrology

138

146

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Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

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“…COXs catalyze the oxidative metabolism of arachidonic acid into prostaglandin H2, which is the precursor of other prostaglandins including prostaglandin G2 (PEG2) [48,49]. PEG2 has been reported to inhibit Fas-induced apoptosis and markedly increase expression of Mcl-1 in KMBC cholangiocarcinoma cells [50].…”

Section: Discussionmentioning

confidence: 99%

Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin

Shi

Fan²,

Cai³

et al. 2012

neo

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The flavonol aglycone isorhamnetin shows anti-proliferative activity in a variety of cancer cells. Previous work, from our laboratory showed that isorhamnetin inhibits the proliferation of human esophageal squamous carcinoma Eca-109 cells in vitro, but only after 72 h of exposure. This led us to propose that isorhamnetin exposure induces a cellular stress response that inhibits the antiproliferative and apoptotic effects of the compound during early exposure. To test this hypothesis, the present study examined the effects of isorhamnetin on Eca-109 cells during the first 72 h of exposure. Cell growth was assessed using the trypan blue exclusion assay, and expression of IκBα, NF-κB/p65, NF-κB/p50, phospho-Akt, Bcl-2, COX-2, Mcl-1, Bax, p53 and Id-1 were analyzed by Western blot. During the first 72 h of exposure, NF-κB/p65 and NF-κB/p50 accumulated in nuclei and expression of COX-2, Bcl-2 and Mcl-1 increased. In contrast, expression of IκBα and Bax fell initially but later increased. Expression of phospho-Akt and p53 showed no detectable change during the first 48 h. Pretreatment with the NF-κB inhibitor MG132 before exposure to isorhamnetin blocked the nuclear accumulation of p50 and p65, thereby inhibiting cell proliferation. These results show that during early exposure of Eca-109 cells to isorhamnetin, the NF-κB signaling pathway is activated and COX-2 expression increases, and this increase in expression partially inhibits isorhamnetin-induced apoptosis. Beyond 72 h of exposure, however, the apoptotic effect of isorhamnetin dominates, leading to inhibition of the NF-κB pathway and of cellular proliferation. These results will need to be taken into account when exploring the use of isorhamnetin against cancer in vivo.

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Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-γ in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-κB

Cited by 60 publications

References 36 publications

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin

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