Fenofibrate antagonizes Chk2 activation by inducing Wip1 expression: Implications for cell proliferation and tumorigenesis

Joe, Yeonsoo; Do, Mihyang; Seo, Eunhui; Kang, Soojeong; Park, Hwan-Tae; Yun, Jeanho; Lee, Hye Jeong

doi:10.1016/j.lfs.2010.03.006

Cited by 3 publications

(4 citation statements)

References 23 publications

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“…By activating PPAR α , fenofibrate also inhibited IFN- γ , the Th1 cytokine expression by activated cells [19, 21]. In addition, fenofibrate has also been found to exert some functions independent of PPAR α activation, including exacerbating left ventricular dilation and fibrosis in chronic pressure overload [29], inhibiting the production of cysteinyl leukotriene in mast cells [30], improving the survival of retinal endothelial cells [31], reducing the expression of plasminogen activator inhibitor type-I in progressive fibrosing steatohepatitis liver cells [32] and promoting the proliferation of liver cells [33]. In the present study, repressing Th17 cell differentiation might be another PPAR α -independent function of fenofibrate, despite the present finding that activating multiple nuclear receptors with their ligands ameliorate the differentiation of Th17 cells, such as RAR [34], RXR [34], AHR [35], LXR [36], and even two other members of PPAR family, PPAR γ and PPAR β / δ [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

et al. 2012

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Uncontrolled activity of T cells mediates autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and atherosclerosis. Recent findings suggest that enhanced activity of interleukin-17 (IL-17) producing T helper 17 cells (Th17 cells) plays an important role in autoimmune diseases and inflammatory diseases. Previous papers have revealed that a lipid-lowering synthetic ligand of peroxisome proliferator-activated receptor α (PPARα), fenofibrate, alleviates both atherosclerosis and a few nonlipid-associated autoimmune diseases such as autoimmune colitis and multiple sclerosis. However, the link between fenofibrate and Th17 cells is lacking. In the present study, we hypothesized that fenofibrate inhibited the differentiation of Th17 cells. Our results showed that fenofibrate inhibited transforming growth factor-β (TGF-β) and IL-6-induced differentiation of Th17 cells in vitro. However, other PPARα ligands such as WY14643, GW7647 and bezafibrate did not show any effect on Th17 differentiation, indicating that this effect of fenofibrate might be PPARα independent. Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

et al. 2012

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“…Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro (Wilk et al, 2012). It was also reported that fenofibrate suppressed cell proliferation by regulating the cell cycle such as inducing G0/G1 arrest (Wilk et al, 2012;Zhao et al, 2013;Liang et al, 2013;Watanabe et al, 2013;Li et al, 2014) or G2/M arrest (Urbanska et al, 2008;Joe et al, 2010). In spite of these multiple observations, molecular mechanisms by which fenofibrate targets cancer cells are not well defined.…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

Liu¹,

Ge²,

Zhu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Radiation therapy is an important treatment for head and neck squamous cell carcinoma (HNSCC). However, how to promote radiation sensitivity in HNSCC remains a challenge. This study aimed to investigate the radiosensitizing effects of fenofibrate on HNSCC and explore the underlying mechanisms. HNSCC cell lines CNE-2 and KB were subjected to ionizing radiation (IR), in the presence or absence of fenofibrate treatment. Cell growth and survival, apoptosis and cell cycle were evaluated. In addition, CNE-2 cells were xenografted into nude mice and subjected to IR and/ or fenofibrate treatment. The expression of cyclinB and CDK1 was detected by Western blotting. Our results showed that fenofibrate efficiently radiosensitized HNSCC cells and xenografts in mice, and induced apoptosis and G2/M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex. These data suggest that fenofibrate could be a promising radiosensitizer for HNSCC radiotherapy.

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“…Fenofibrate is a member of fibric acid compounds and is widely used in lipid-lowering drugs for the treatment of various lipid diseases. Some studies have shown that fenofibrate can stimulate the development of liver cancer in rodents, [14][15][16] so we want to evaluate the stimulation of SMMC-7721 cells proliferation by fenofibrate, and SMMC-7721 is a human liver cancer cell line.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Fenofibrate drugs can also have toxic effects, including obvious peroxisome proliferation and carcinogenic effects on rodents. [14][15][16] According to information released by the US Food and Drug Administration (FDA), fenofibrate at a concentration of 200 mg/kg increases the incidence of liver cancer in rats and mice. Recently, Kawai et al also reported that fenofibrate increased the number of pre-tumor lesions in rasH2 mice (this model was created by microinjecting the human c-Ha-ras gene into C57BL/6 x BALB/c F2 zygotes).…”

Section: Introductionmentioning

confidence: 99%

Effect of fenofibrate on proliferation of SMMC-7721 cells via regulating cell cycle

Jiang

et al. 2021

Hum Exp Toxicol

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Liver cancer is a malignant cancer with great harmfulness. Fenofibrate is a peroxisome proliferation activated receptor (PPARα) agonist widely used in the treatment of dyslipidemia. Previous studies have shown that fenofibrate may promote cell proliferation, but the underlying mechanism has not been fully characterized. The aim of this study was to investigate the role of PPARα agonist fenofibrate in cell proliferation of SMMC-7721 cells compared with that of THLE-2 cells. SMMC-7721 and THLE-2 cells were treated with different concentrations of fenofibrate. Cell proliferation was analyzed by MTT, using flow cytometry for cell cycle analysis, and CyclinD1, Cyclin-dependent kinases2 (CDK2) and Proliferating Cell Nuclear Antigen (PCNA) were analyzed by Western blotting. RT-qPCR method was used to assess CDK2, CyclinD1 and PCNA mRNA levels. The results showed that 10−9–10−4 mol/L fenofibrate could induce cell growth and 10−4, 10−5, 10−6 mol/L fenofibrate could reduce the number of G0/G1 phase cells and increased in the number of cells in S and G2/M phase of cell cycle in SMMC-7721 cells. Furthermore, fenofibrate could significantly increase the expression of cell cycle related protein (CyclinD1, CDK2)and cell proliferation related proteins (PCNA). The use of PPARα inhibitor MT886 inhibited cell cycle progression and promote tumor cell apoptosis. But fenofibrate had no obvious effect on THLE-2 cells. These results revealed the effect of fenofibrate on the cell cycle of liver cancer cells, and provided a reasonable explanation for studying how fenofibrate promotes cell proliferation.

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Fenofibrate antagonizes Chk2 activation by inducing Wip1 expression: Implications for cell proliferation and tumorigenesis

Cited by 3 publications

References 23 publications

Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

Effect of fenofibrate on proliferation of SMMC-7721 cells via regulating cell cycle

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