Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells

Araki, Hiromitsu; Tamada, Yoshinori; Imoto, Seiya; Dunmore, Ben; Sanders, Deborah A.; Humphrey, Sally; Nagasaki, Masao; Doi, Akira; Nakanishi, Yusuke; Yasuda, Kaori; Tomiyasu, Yuki; Tashiro, Kousuke; Print, Cristin G.; Charnock-Jones, D. Stephen; Kuhara, Satoru; Miyano, Satoru

doi:10.1007/s10456-009-9142-8

Cited by 33 publications

(34 citation statements)

References 33 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Expression of GDF15 and miR-3189-3p Is Increased after Fenofibrate Treatment-Previous reports have demonstrated that GDF15 expression is induced following treatment by a variety of chemotherapeutic agents (13,21,22). In line with these findings, we have also reported that this gene is up-regulated in a microarray analysis of glioblastoma cells treated with the metabolically active anticancer compound fenofibrate (4).…”

Section: Role Of Sf3b2 and P63rhogef In The Inhibition Of Cellular Prsupporting

confidence: 85%

“…Similarly, anti-miR-3189-3p did not protect fenofibrate-treated cells from apoptosis, indicating that up-regulation of miR-3189-3p is not required for fenofibrate-mediated cell death. Given the broad range of anticancer effects triggered by fenofibrate (5,6,22,23,32,33) and the activity of a single microRNA, it is not surprising that miR-3189-3p is not contributing to the massive cell death mediated by fenofibrate. The microRNA itself seems to have a cytostatic rather than cytotoxic effect on the cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-tumoral Effects of miR-3189-3p in Glioblastoma

Jeansonne

DeLuca

Marrero

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Section: Role Of Sf3b2 and P63rhogef In The Inhibition Of Cellular Prsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Anti-tumoral Effects of miR-3189-3p in Glioblastoma

Jeansonne

DeLuca

Marrero

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Several reports indicate that FF may act in a PPAR␣-independent manner (5,12,14,18,20,30,37). To analyze these off-target effects, we subjected LN-229 human glioblastoma cells and NHA to subcellular fractionation following treatment with 50 M FF.…”

Section: Resultsmentioning

confidence: 99%

“…However, in comparison with the anticancer effects of other potent agonists of PPAR␣, those of FF are much more pronounced, implying that FF may also act in a PPAR␣-independent manner. In this regard, FF was shown to alter the expression of growth differentiation factor 15 (20); affect cell membrane fluidity in a manner similar to that of cholesterol (30); and interfere with the respiratory function of isolated liver and heart mitochondria (31,32). Here we report the novel observation that FF, but not its PPAR␣-active metabolite FA, accumulates in the mitochondrial fraction of human glioblastoma cells.…”

mentioning

confidence: 80%

“…In this process, FF must first be converted to fenofibric acid (FA) by blood and tissue esterases. FA then binds and activates PPAR␣, which triggers the expression of numerous metabolic enzymes involved in fatty acid ␤-oxidation (18)(19)(20). In addition, activated PPAR␣ decreases glucose uptake by repressing the insulin-dependent glucose transporter GLUT4 (19,21) and elevated oxidation of the fatty acids and ketone bodies further suppresses the expression of glycolytic enzymes (22,23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Wilk

Wyczechowska

Zapata

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

e Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR␣). FF and several other agonists of PPAR␣ have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPAR␣-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPAR␣-dependent metabolic switch from glycolysis to fatty acid ␤-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. F enofibrate (FF) is a common lipid-lowering drug and a potent agonist of peroxisome proliferator-activated receptor alpha (PPAR␣). Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1-7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8). In cell culture and animal studies, various members of the fibrate family, which are all agonists of PPAR␣, demonstrate interesting anticancer effects, which are not fully understood. FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9, 10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients wit...

show abstract

Fenofibrate inhibits TGF‐β‐induced myofibroblast differentiation and activation in human lung fibroblasts in vitro

et al. 2021

View full text Add to dashboard Cite

Fenofibrate (FF), a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist and a lipid-lowering agent, can decrease experimental pulmonary fibrosis. However, the mechanisms underlying the anti-fibrotic effect of FF remain unknown. Hence, this study was conducted to evaluate the effects of FF on transforming growth factor-beta (TGF--induced myofibroblast differentiation and activation in lung fibroblasts. The results showed that FF inhibited alpha-smooth muscle actin (α-SMA) and connective-tissue growth-factor expression, collagen production, cell motility, SMAD3 phosphorylation and nuclear translocation, and metabolic reprogramming in TGF--exposed cells. The inhibitory effect of FF did not decrease with the addition of a PPAR-α antagonist. Moreover, the inhibitory effect given by FF could not be reproduced with the addition of an alternative PPAR-α agonist. FF inhibited mitochondrial respiration. However, rotenone, a complex I inhibitor, did not suppress TGF--induced myofibroblast differentiation. Furthermore, the TGF--induced nuclear reduction of protein phosphatase, Mg 2+ /Mn 2+ -dependent 1A (PPM1A), a SMAD phosphatase, was inhibited by FF.These results showed that FF suppressed TGF--induced myofibroblast differentiation and activation independent of PPAR-α activation and impaired mitochondrial respiration. In conclusion, this study provides information on the effects of FF on anti-TGF- mechanisms.

show abstract

Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells

Cited by 33 publications

References 33 publications

Anti-tumoral Effects of miR-3189-3p in Glioblastoma

Anti-tumoral Effects of miR-3189-3p in Glioblastoma

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Fenofibrate inhibits TGF‐β‐induced myofibroblast differentiation and activation in human lung fibroblasts in vitro

Contact Info

Product

Resources

About