Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations

Madeja, Zbigniew

doi:10.3892/or.2011.1321

Cited by 16 publications

(10 citation statements)

References 36 publications

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“…Our data show that FF efficiently interferes with communication networks between lung cancer and endothelial cells, thus potentially inhibiting lung cancer progression. They are consistent with the long list of inhibitory effects of FF on the malignancy of glioma/glioblastoma [ 29 , 40 ], hepatoma [ 30 , 41 ], medulloblastoma [ 42 ], melanoma [ 25 , 43 ], and prostate cancer cells [ 44 ]. Concomitant augmentation of the endothelial barrier function during the diapedesis can additionally reduce the risk of lung cancer metastases.…”

Section: Discussionsupporting

confidence: 86%

Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling

Piwowarczyk

Kwiecień

Sośniak

et al. 2018

Cancers

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Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect of fenofibrate (FF) on their activity. A549 cells induced the disruption and local activation of endothelial continuum. These events were accompanied by epidermal growth factor (EGF) up-regulation in endothelial cells. Impaired A549 diapedesis and HUVEC activation were seen upon the chemical inhibition of connexin(Cx)43 functions, EGF/ERK1/2-dependent signaling, and RhoA/Rac1 activity. A total of 25 μM FF exerted corresponding effects on Cx43-mediated gap junctional coupling, EGF production, and ERK1/2 activation in HUVEC/A549 co-cultures. It also directly augmented endothelial barrier function via the interference with focal adhesion kinase (FAK)/RhoA/Rac1-regulated endothelial cell adhesion/contractility/motility and prompted the selective transmigration of epithelioid A549 cells. N-acetyl-L-cysteine abrogated FF effects on HUVEC activation, suggesting the involvement of PPARα-independent mechanism(s) in its action. Our data identify a novel Cx43/EGF/ERK1/2/FAK/RhoA/Rac1-dependent signaling axis, which determines the efficiency of lung cancer cell diapedesis. FF interferes with its activity and reduces the susceptibility of endothelial cells to A549 stimuli. These findings provide the rationale for the implementation of FF in the therapy of malignant lung cancers.

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Section: Discussionsupporting

confidence: 86%

Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling

Piwowarczyk

Kwiecień

Sośniak

et al. 2018

Cancers

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“…The anti-proliferation and apoptosis-inducing effects of fenofibrate in TNBC were independent on PPAR-α status, which was also reported in B-cell lymphoma [5], prostate cancer [31], hepatocellular carcinoma [10], mantle cell lymphoma [8] and endometrial cancer [17]. However, the PPAR-α dependent mechanisms were used to explain the anti-cancer effects of fenofibrate in glioma [12], glioblastoma [7] and melanoma [14].…”

Section: Discussionmentioning

confidence: 56%

Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway

Zhang

et al. 2014

BMC Cancer

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BackgroundThere are a lot of unmet needs in patients with triple-negative breast cancer (TNBC). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, has been used for decades to treat hypertriglyceridaemia and mixed dyslipidaemia. Recent studies show that it might have anti-tumor effects, however, the mechanism remains unclear. Here, we assessed the ability of fenofibrate to induce apoptosis of TNBC in vitro and in vivo and explored involved mechanisms.MethodsMTT method was used to evaluate the anti-proliferation effect of fenofibrate, and invert microscope to observe the apoptotic morphological changes. The percentage of apoptotic cells and distribution ratios of cell cycle were determined by flow cytometric analysis. The related protein levels were measured by Western blot method. The changes of genes and pathways were detected by gene expression profiling. The tumor growth in vivo was assessed by MDA-MB-231 xenograft mouse model. Terminal deoxytransferase-catalyzed DNA nick-end labeling (TUNEL) assay was employed to estimate the percentage of apoptotic cells in vivo. In order to evaluate the safety of fenofibrate, blood sampled from rat eyes was detected.ResultsWe found that fenofibrate had anti-proliferation effects on breast cancer cell lines, of which the first five most sensitive ones were all TNBC cell lines. Its induction of apoptosis was independent on PPAR-α status with the highest apoptosis percentage of 41.8 ± 8.8%, and it occurred in a time- and dose-dependent manner accompanied by up-regulation of Bad, down-regulation of Bcl-xl, Survivin and activation of caspase-3. Interestingly, activation of NF-κB pathway played an important role in the induction of apoptosis by fenofibtate and the effect could be almost totally blocked by a NF-κB specific inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, fenofibrate led to cell cycle arrest at G0/G1 phase accompanied by down-regulation of Cyclin D1, Cdk4 and up-regulation of p21, p27/Kip1. In vivo, fenofibrate slowed down tumor growth and induced apoptosis with a good safety profile in the MDA-MB-231 xengograft mouse model.ConclusionsIt is concluded that fenofibrate induces apoptosis of TNBC via activation of NF-κB pathway in a PPAR-α independent way, and may serve as a novel therapeutic drug for TNBC therapy.

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“…Meanwhile, the effect of fenofibrate on DU-145 cell motility was PPARα-independent, because GW9662, which effectively inhibits both PPARγ and PPARα, did not restore the motility of DU-145 cells suppressed by fenofibrate. Furthermore, fenofibrate increased the ROS accumulation in DU-145 cells, whereas NAC partially restored cell motility and gap junctional coupling in fenofibrate-treated DU-145 cell 56 .…”

Section: Anticancer Activity: In Vitro Studiesmentioning

confidence: 90%

Anticancer Properties of Fenofibrate: A Repurposing Use

et al. 2018

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Cancer is a leading cause of death throughout the world, and cancer therapy remains a big medical challenge in terms of both its therapeutic efficacy and safety. Therefore, to find out a safe anticancer drug has been long goal for oncologist and medical scientists. Among clinically used medicines with no or little toxicity, fenofibrate is a drug of the fibrate class that plays an important role in lowering the levels of serum cholesterol and triglycerides while elevating the levels of high-density lipoproteins. Recently, several studies have implied that fenofibrate may exert anticancer effects via a variety of pathways involved in apoptosis, cell-cycle arrest, invasion, and migration. Given the great potential that fenofibrate may have anticancer effects, this review was to investigate all published works which directly or indirectly support the anticancer activity of fenofibrate. These studies provide evidence that fenofibrate exerted antitumor effects in several human cancer cell lines, such as breast, liver, glioma, prostate, pancreas, and lung cancer cell lines. Among these studies some have further confirmed the possibility and efficacy of fenofibrate anticancer in xenograft mouse models. In the last part of this review, we also discuss the potential mechanisms of action of fenofibrate based on the available information. Overall, we may repurpose fenofibrate as an anticancer drug in cancer treatment, which urgently need further and comprehensively investigated.

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Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations

Cited by 16 publications

References 36 publications

Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling

Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling

Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway

Anticancer Properties of Fenofibrate: A Repurposing Use

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