PPARα signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells

Tuller, Erin; Brock, Andrea L.; Yu, Haijun; Lou, Jessica R.; Benbrook, Doris M.; Ding, Wei

doi:10.1016/j.bcp.2009.02.002

Cited by 34 publications

(32 citation statements)

References 43 publications

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“…Western blot analysis with specific antibodies confirmed that PPAR␥ and PPAR␣ are expressed in A2780 cells (Tuller et al, 2009). Furthermore, HIF-2␣ is constitutively expressed in this cell line, whereas HIF-1␣ is not detectable in the presence and absence of DHA.…”

Section: Ppar␣ Ligand Mimics the Effects Of Dha On Sod-1 Gene Transcrmentioning

confidence: 79%

Docosahexaenoic Acid Inhibits Superoxide Dismutase 1 Gene Transcription in Human Cancer Cells: The Involvement of Peroxisome Proliferator-Activated Receptor α and Hypoxia-Inducible Factor-2α Signaling

et al. 2009

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Docosahexaenoic acid (DHA; 22:6) is known to have anticancer activity, but its mechanisms of action remain to be further elucidated. We recently demonstrated that DHA downregulates superoxide dismutase (SOD) 1 gene expression, thereby weakening cellular antioxidant forces and enhancing cytotoxicity in various human cancer cells. The objective of this study was to investigate the mechanism of the inhibitory effect of DHA on SOD-1 gene expression in human cancer cells. A reporter gene assay indicated that DHA suppresses SOD-1 gene transcription in a time-and concentration-dependent manner in human cancer cells. Pretreatment with vitamin E did not block the inhibitory effect of DHA, indicating that this suppression does not depend on lipid peroxidation. The suppressive effect of DHA on SOD-1 gene transcription could be mimicked by the peroxisome proliferator-activator receptor (PPAR) ␣ ligand clofibrate but not the PPAR␥ ligand troglitazone, suggesting the involvement of PPAR␣ signaling. Deletion analysis of the key DNA binding elements in the SOD-1 gene promoter identified the distal hypoxia response element (HRE), but not the peroxisome proliferator response element or nuclear factor-B element, as essential for the suppressive effects of DHA. Coimmunoprecipitation confirmed that PPAR␣, but not PPAR␥, forms a complex with hypoxia-inducible factor (HIF)-2␣ in cancer cells. Chromatin immunoprecipitation analysis indicated that both DHA and clofibrate reduce HIF-2␣ binding to the HRE. Thus, we have identified the distal HRE in the SOD-1 gene promoter that mediates the suppression on the transcription of this gene by DHA, and we have demonstrated the involvement of PPAR␣ and HIF-2␣ signaling in this event.

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Section: Ppar␣ Ligand Mimics the Effects Of Dha On Sod-1 Gene Transcrmentioning

confidence: 79%

Docosahexaenoic Acid Inhibits Superoxide Dismutase 1 Gene Transcription in Human Cancer Cells: The Involvement of Peroxisome Proliferator-Activated Receptor α and Hypoxia-Inducible Factor-2α Signaling

et al. 2009

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“…Recent studies demonstrated that these two drugs have anticancer properties in various model systems (9 -11), but the mechanisms behind their actions remain to be elucidated. We have reported previously that activation of PPAR␣ mediates the anticancer action of docosahexaenoic acid, likely through down-regulation of hypoxia signaling (12,13). We therefore hypothesized that the anticancer properties of PPAR␣ agonists may similarly be due to suppression of HIF-1␣ signaling in human cancer cells.…”

Section: Activation Of Peroxisome Proliferator-activated Receptor ␣ (mentioning

confidence: 97%

“…Cells-To understand whether the PPAR␣ ligands clofibrate and fenofibrate activate PPAR␣ signaling in MCF-7 cells, cells were transfected with 3 g of the peroxisome proliferator response element-luciferase plasmid construct and 1 g of RXR␣ cDNA (13) and treated with 500 M clofibrate, 100 M fenofibrate (two established PPAR␣ agonists), or 20 M troglitazone (a PPAR␥ agonist) for 4 h. The concentrations of the compounds were chosen according to previous studies (20,21). As expected, all three compounds activated peroxisome proliferator response element-driven reporter gene activity in MCF-7 cells (Fig.…”

Section: Activation Of Ppar␣ By Clofibrate and Fenofibrate In Mcf-7mentioning

confidence: 99%

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

Zhou

Zhang

Xue

et al. 2012

Journal of Biological Chemistry

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Background:The mechanisms of PPAR␣-mediated inhibition of tumor growth and angiogenesis remain unknown. Results: Activation of PPAR␣ suppresses hypoxia-induced HIF-1␣ signaling via promoting HIF-1␣ degradation and diminishes hypoxia-induced VEGF secretion from cancer cells and tube formation by endothelial cells. Conclusion: Activation of PPAR␣ suppresses the HIF-1␣ signaling pathway in cancer cells. Significance: The results support the development of PPAR␣ agonists as anticancer agents.

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“…Therefore, further characterization of clofibrate's biological activity in cancer cells and its interaction with cancer related molecules will facilitate the development of this compound as well as other fibrates into clinical oncology practice. 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].…”

Section: Introductionmentioning

confidence: 99%

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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PPARα signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells

Cited by 34 publications

References 43 publications

Docosahexaenoic Acid Inhibits Superoxide Dismutase 1 Gene Transcription in Human Cancer Cells: The Involvement of Peroxisome Proliferator-Activated Receptor α and Hypoxia-Inducible Factor-2α Signaling

Docosahexaenoic Acid Inhibits Superoxide Dismutase 1 Gene Transcription in Human Cancer Cells: The Involvement of Peroxisome Proliferator-Activated Receptor α and Hypoxia-Inducible Factor-2α Signaling

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

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

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