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Apoptotic effect of the selective PPARβ/δ agonist GW501516 in invasive bladder cancer cells

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Tumor Biology

Abstract

GW501516 is a selective and high-affinity synthetic agonist of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). This molecule promoted the inhibition of proliferation and apoptosis in few cancer cell lines, but its anticancer action has never been investigated in bladder tumor cells. Thus, this study was undertaken to determine whether GW501516 had antiproliferative and/or apoptotic effects on RT4 and T24 urothelial cancer cells and to explore the molecular mechanisms involved. Our results indicated that, in RT4 cells (derived from a low-grade papillary tumor), GW501516 did not induce cell death. On the other hand, in T24 cells (derived from an undifferentiated high-grade carcinoma), this PPARβ/δ agonist induced cytotoxic effects including cell morphological changes, a decrease of cell viability, a G2/M cell cycle arrest, and the cell death as evidenced by the increase of the sub-G1 cell population. Furthermore, GW501516 triggered T24 cell apoptosis in a caspase-dependent manner including both extrinsic and intrinsic apoptotic pathways through Bid cleavage. In addition, the drug led to an increase of the Bax/Bcl-2 ratio, a mitochondrial dysfunction associated with the dissipation of ΔΨm, and the release of cytochrome c from the mitochondria to the cytosol. GW501516 induced also ROS generation which was not responsible for T24 cell death since NAC did not rescue cells upon PPARβ/δ agonist exposure. For the first time, our data highlight the capacity of GW501516 to induce apoptosis in invasive bladder cancer cells. This molecule could be relevant as a therapeutic drug for high-grade urothelial cancers.

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Acknowledgments

This work was supported by research grants from the Ligue Nationale Contre le Cancer (CCIR-GE) and the LabEx LipSTIC. We thank Julie Frejaville for technical assistance and Virginie Mougey for her help for the flow cytometry analyses.

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Authors and Affiliations

  1. EA3181, SFR FED4234, University of Bourgogne Franche-Comté, 25030, Besançon Cedex, France

    Adeline Péchery, Sylvie Fauconnet, Hugues Bittard & Isabelle Lascombe

  2. University Hospital of Besançon, 25030, Besançon Cedex, France

    Sylvie Fauconnet & Hugues Bittard

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  1. Adeline Péchery
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  2. Sylvie Fauconnet
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  3. Hugues Bittard
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  4. Isabelle Lascombe
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Correspondence to Isabelle Lascombe.

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Adeline Péchery and Sylvie Fauconnet contributed equally to this work.

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Péchery, A., Fauconnet, S., Bittard, H. et al. Apoptotic effect of the selective PPARβ/δ agonist GW501516 in invasive bladder cancer cells. Tumor Biol. 37, 14789–14802 (2016). https://doi.org/10.1007/s13277-016-5305-6

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  • DOI: https://doi.org/10.1007/s13277-016-5305-6

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