Expression of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) in Human Non-small Cell Lung Carcinoma: Correlation with Clinicopathological Parameters, Proliferation and Apoptosis Related Molecules and Patients’ Survival

Giaginis, Constantinos; Politi, Ekaterini; Alexandrou, Paraskevi; Sfiniadakis, J; Kouraklis, Gregory; Theocharis, Stamatios

doi:10.1007/s12253-012-9517-9

Cited by 30 publications

(30 citation statements)

References 58 publications

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“…Among them, PPARγ plays an important role in the regulation of various biological functions, such as lipid homeostasis, adipogenesis, inflammation, and cancer biology. PPARγ has been shown to be expressed in several types of human malignancies, including lung cancer [4, 5]. Large bodies of evidence have demonstrated anti-proliferative and pro-apoptotic effects of PPARγ agonists suggesting that PPARγ could be considered as a potential target for the treatment of cancers [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

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Background: Emodin has anti-neoplastic activities on multiple tumors. However, the molecular mechanisms underlying this effect still remain to be fully understood. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. Cell invasion and migration were examined by transwell invasion and wound healing assays. Western blot analysis was performed to examine the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα), extracellular signaling-regulated kinase 1/2 (ERK1/2), peroxisome proliferators-activated receptor gamma (PPARγ), insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and the transcription factor Sp1. QRT-PCR was used to examine the mRNA levels of the IGFBP1 gene. Small interfering RNAs (siRNAs) were used to knockdown PPARγ and IGFBP1 genes. Exogenously expression of IGFBP1 and Sp1 was determined by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings. Results: We showed that emodin induced cell cycle arrest of NSCLC cells. Emodin increased PPARγ protein and luciferase reporter activity, which were abolished by inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK)/ERK and AMPK. Silencing of PPARγ abrogated emodin-inhibited cell growth and cell cycle arrest. Furthermore, emodin elevated IGFBP1 mRNA, protein, and promoter activity through activation of PPARγ. Intriguingly, overexpressed Sp1 attenuated emodin-induced IGFBP1 expression, which was not observed in cells with silenced PPARγ gene. Moreover, silencing of IGFBP1 gene blunted emodin-induced inhibition of cell growth and cell cycle arrest. On the contrary, overexpressed IGFBP1 enhanced emodin-induced phosphorylation of AMPKα and ERK1/2, and restored emodin-inhibited growth in cells with silenced endogenous IGFBP1 gene. Emodin also inhibited growth of lung xenograft tumors and Sp1, and increased IGFBP1 and PPARγ protein expressions In vivo. Conclusion: Collectively, our results show that emodin inhibits growth of non-small-cell lung cancer (NSCLC) cells through ERK and AMPKα-mediated induction of PPARγ, followed by reduction of Sp1. This in turn induces IGFBP1 gene expression. Thus, the signaling cascades, positive feedback loop and cooperative interplay between transcription factors-induced the expression of IGFBP1 gene contribute to the overall responses of emodin. This study provides a novel mechanism by which emodin inhibits growth of human lung cancer cells.

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Section: Introductionmentioning

confidence: 99%

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

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“…Published data suggest a beneficial role for PPARγ ligands in lung cancer (42). PPARγ is upregulated in human lung cancer (43) and activation of PPARγ by troglitazone inhibits lung cancer cell growth (44). Thiazolidinediones, a group of PPARγ activating drugs, are associated with a lower risk of developing lung cancer (45), prevent smoke-induced lung cancer in mice, and together with glucocorticoids prevent carcinogen-induced lung cancer in rodents (46, 47).…”

Section: Discussionmentioning

confidence: 99%

PPARα Activation Can Help Prevent and Treat Non–Small Cell Lung Cancer

Skrypnyk

Chen

et al. 2014

Cancer Research

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Non-small cell lung cancer (NSCLC) not amenable to surgical resection has a high mortality rate, due to the ineffectiveness and toxicity of chemotherapy. Thus, there remains an urgent need of efficacious drugs that can combat this disease. In this study, we show that targeting the formation of pro-angiogenic epoxyeicosatrienoic acids (EETs) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. In the transgenic murine K-Ras model and human orthotopic models of NSCLC, we found that Cyp2c44 could be downregulated by activating the transcription factor PPARα with the ligands bezafibrate and Wyeth-14,643. Notably, both treatments reduced primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression and circulating EET levels. These beneficial effects were independent of the time of administration, whether before or after the onset of primary NSCLC, and they persisted after drug withdrawal, suggesting the benefits were durable. Our findings suggest that strategies to downregulate Cyp2c expression and/or its enzymatic activity may provide a safer and effective strategy to treat NSCLC. Moreover, as bezafibrate is a well-tolerated clinically approved drug used for managing lipidemia, our findings provide an immediate cue for clinical studies to evaluate the utility of PPARα ligands as safe agents for the treatment of lung cancer in humans.

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“…Perinuclear staining was found in endometrial cancer (Knapp et al, 2012). However, in breast cancer, medulloblastoma, skin melanoma cells, and lung cancer, cytoplasmic staining was reported and/or illustrated (Bhatia et al, 2012; Freudlsperger et al, 2006; Giaginis et al, 2012; Papadaki et al, 2005). Upon mitogenic stimulation, a MAPK/ERK kinase-dependent shuttle may be involved in nuclear export of PPAR-gamma (Burgermeister et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles

Herwig

Bergstrom

Wells

et al. 2013

Experimental Eye Research

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Macrophages have been found to be negative predictors of outcome in patients with uveal melanoma. In particular, recent studies point towards a disease-progressing role of proangiogenic M2 macrophages in melanomas with monosomy 3. Although most studies implicate a protective effect of PPAR-gamma activation in tumors, PPAR-gamma has also been shown to promote the polarization of M1 macrophages towards the M2 phenotype. The purpose of this investigation was first, to characterize the phenotype of tumor infiltrating macrophages and second, to study PPAR-gamma expression in uveal melanomas with molecular gene expression profile as prognostic predictors for patients’ outcome. Twenty specimens from patients with uveal melanoma were analyzed for clinical and histologic tumor characteristics. The molecular RNA profile (class 1 or class 2) was commercially determined. Using immunohistochemical techniques, the specimens were dual labeled for CD68 and CD163. CD68+CD163− M1 macrophages and CD68+CD163+ M2 macrophages were analyzed in ten high power fields sparing macrophage-poor areas and a mean value was calculated for each tumor. The tumors were immunostained for von Willebrand factor and the mean vascular density (MVD) was analyzed according to Foss. To assess the proliferative rate of each tumor, Ki67 expression was evaluated in ten high power fields followed by calculation of a mean value. Expression of PPAR-gamma was evaluated using a score from 0 (no staining) to 3 (tumor entirely stained). Statistical analysis and a respective correlation was made between histologic characteristics, molecular profile, type of tumor infiltrating macrophages (M1 versus M2), MVD, proliferative rate, and PPAR-gamma expression. Our results showed a correlation between the ratio of M2/M1 macrophages and the molecular profile with a ratio of approximately 1 corresponding to molecular class 1 and a ratio of approximately 2 corresponding to molecular class 2 (p=0.01). The ratio of M2/M1 macrophages was higher in tumors with extraocular extension (p=0.01). PPAR-gamma was predominantly expressed in the cytoplasm of tumor cells. Its expression showed no association with the molecular RNA profile (p=0.83). This study confirmed that the ratio of M2/M1 macrophages is another prognostic factor in uveal melanoma. Thus, polarization of macrophages plays an important role for patients’ outcome. PPAR-gamma is expressed in uveal melanoma tumor cells and further studies are warranted to determine its role in tumor biology.

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Expression of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) in Human Non-small Cell Lung Carcinoma: Correlation with Clinicopathological Parameters, Proliferation and Apoptosis Related Molecules and Patients’ Survival

Cited by 30 publications

References 58 publications

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

PPARα Activation Can Help Prevent and Treat Non–Small Cell Lung Cancer

M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles

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