4.7 Article

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

Journal

ISCIENCE
Volume 25, Issue 1, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.isci.2021.103571

Keywords

-

Funding

  1. Cancer Australia [1107743]
  2. Cancel Council WA and iCare Dust Diseases Care
  3. NHMRC
  4. Simon Lee Foundation
  5. Cancer Council of Western Australia
  6. University Postgraduate Award
  7. Australian Government Research Training Program Scholarships at The University of Western Australia
  8. Metabolomics Australia
  9. NCRIS capability under Bioplatforms Australia Pty Ltd.
  10. University, State, and Commonwealth Governments

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The study found that increased activity of PPAR alpha and PPAR gamma is associated with the development of mesothelioma. However, a dual PPAR alpha/gamma antagonist is not a viable treatment for the cancer.
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 PPAR alpha and PPAR gamma and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPAR alpha/gamma 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 PPAR alpha/gamma 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 PPAR alpha/gamma antagonism alone is not a viable treatment modality for mesothelioma.

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