Document Type
Journal Article
Publication Title
iScience
Volume
25
Issue
1
Publisher
Elsevier
School
School of Science
RAS ID
40608
Funders
Funding information :
https://doi.org/10.1016/j.isci.2021.103571
National Health and Medical Research Council
Abstract
Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumors displayed a transcriptional signature consistent with increased activity of nuclear receptors PPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.
DOI
10.1016/j.isci.2021.103571
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Morales, M. L. O., Rinaldi, C. A., de Jong, E., Lansley, S. M., Gummer, J. P. A., Olasz, B., . . . Lesterhuis, W. J. (2022). PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective. iScience, 25(1), article 103571.
https://doi.org/10.1016/j.isci.2021.103571