Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells

Zhou, Jundong; Zhang, Shuyu; Xue, Jing; Avery, Jori E.; Wu, Jinchang; Lind, Stuart E.; Ding, Wei

doi:10.1074/jbc.m112.367367

Cited by 72 publications

(62 citation statements)

References 45 publications

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“…42,58 In turn, HIF-1a enhances transcription of Nox 4. 32 Our results in the OIR retina are consistent with previous findings, suggesting that PPARa likely decreases hypoxia-induced Nox 4 upregulation by accelerating HIF-1a degradation.…”

Section: Discussionmentioning

confidence: 99%

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Moran

Ding

Wang

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Previous studies have demonstrated that peroxisome proliferator-activated receptoralpha (PPARa) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARa's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS.For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARa knockout (PPARa À/À ) mice were exposed to 75% O 2 from postnatal day 7 (P7) to P12 and treated with the PPARa agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl 2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS. Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARaÀ/À OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARa overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-a (HIF-1a) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARa À/À mice.CONCLUSIONS. Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1a/Nox 4 and consequently alleviation of oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Moran

Ding

Wang

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…Studies have shown that fenofibrate can be used to inhibit the growth of several cancer lines, such as colon, breast, endometrial, and skin cancers [7][8][9][10]. Fenofibrate can suppress hypoxiainduced HIF-1α signaling via promoting HIF-1α degradation and diminishing hypoxia-induced VEGF secretion from MCF-7 cells [11].…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate enhances radiosensitivity of esophageal squamous cell carcinoma by suppressing hypoxia-inducible factor-1α expression

Liu

Yang

et al. 2014

Tumor Biol.

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Radiation therapy is widely used in esophageal squamous cell carcinoma (ESCC). Promoting radiation sensitivity is important. Recent studies have shown that fenofibrate can inhibit the growth of several cancer lines and hypoxia-inducible factor-1α (HIF-1α) expression in MCF-7 cells. However, few studies on the radiosensitive effect of fenofibrate on ESCCs under hypoxic condition have been conducted. In this study, we assessed the radiosensitive effects of fenofibrate on human ESCC cells. In vitro experiments showed the inhibition of cytotoxic effects after ionizing irradiation. We measured cell viability and clonogenic survival rate. Flow cytometry showed that fenofibrate pretreatment promoted apoptosis. The in vivo data also suggest that fenofibrate had radiosensitizing effects in ECA-109 cells xenografted into nude mice. Western blot and immunohistochemical analyses revealed that the HIF-1α and vascular endothelial growth factor (VEGF) protein content decreased by fenofibrate. Thus, the inhibition of HIF-1α and VEGF expression in ESCC cells contributed to the radiosensitive effect. These data suggest that fenofibrate may be a potential radiosensitive drug.

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“…The cells were then transfected with the luciferase reporter constructs including the pGL3/4.5-HO-1 and its mutants, the HO-1-3'-UTR and GAPDH-3'-UTR using the Fugene HD transfection reagent (Roche, Mannheim, Germany) as previously described [6]. The next day, cells were lifted and plated into 24-well plates at a density of 2×10 5 per well.…”

Section: Methodsmentioning

confidence: 99%

“…48 hours after transfection, cells were treated with various reagents at indicated concentrations and durations. Cell lysates were prepared and luciferase activity was assayed using the Dual-Luciferase Reporter kit, as previously described [6]. The firefly luciferase activity was normalized to the amount of protein present in each sample.…”

Section: Methodsmentioning

confidence: 99%

“…In this context, we have recently reported that clofibrate acts synergistically with clioquinol, a metal binding compound, to suppress cancer cell viability that is mediated by PPARα signaling [5]. Furthermore, we have shown that clofibrate suppresses hypoxia-induced HIF-1α expression and signaling in breast and ovarian cancer cells, thereby exerting antiangiogenic activity [6]. More interestingly, clofibrate and docosahexaenoic acid, both being PPARα ligands, were found to suppress superoxide dismutase 1 (SOD1) gene expression [7].…”

Section: Introductionmentioning

confidence: 99%

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Clofibrate Induces Heme Oxygenase 1 Expression through a PPARa-Independent Mechanism in Human Cancer Cells

Wang

Hannafon

Zhou

et al. 2013

Cell Physiol Biochem

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Background and Aims: Clofibrate, an established PPARα ligand, has recently been shown to have anticancer activity yet its mechanisms of action remain to be characterized. This study examined the effect of clofibrate on heme oxygenase-1 (HO-1) gene expression in A2780 (human ovarian cancer) and DU145 (human prostate cancer) cells. Methods and Results: We demonstrate that clofibrate induces HO-1 expression in a concentration- and time-dependent manner. The induction of HO-1 by clofibrate was detected at both mRNA and protein levels and the HO-1 gene promoter activity was also dramatically induced by clofibrate, indicating that clofibrate up-regulates HO-1 gene transcription. Surprisingly, the induction of HO-1 by clofibrate was mediated by the Nrf2 signaling pathway, not by the PPARα pathway. This was primarily demonstrated by siRNA knockdown of Nrf2 expression that significantly attenuated clofibrate-induced HO-1 gene transcription, and siRNA knockdown of PPARα that had no effect on clofibrate-induced HO-1 promoter activity. Furthermore, deletion of the antioxidant response elements (AREs) in the HO-1 gene promoter diminished clofibrate-induced HO-1 transcription and deletion of the PPAR response elements (PPREs) had no such effect. Likewise, application of PPARα antagonists had no effect on clofibrate-induced HO-1 expression. Conclusion: Clofibrate induces HO-1 gene expression in cancer cells through a PPARα-independent mechanism and the Nrf2 signaling pathway is indispensible for this induction.

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Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells

Cited by 72 publications

References 45 publications

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Fenofibrate enhances radiosensitivity of esophageal squamous cell carcinoma by suppressing hypoxia-inducible factor-1α expression

Clofibrate Induces Heme Oxygenase 1 Expression through a PPARa-Independent Mechanism in Human Cancer Cells

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