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

Year: 2021

Type: article

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.

Source: iScience

DOI: 10.1016/j.isci.2021.103571

Institutions: The University of Western Australia, The Kids Research Institute Australia, Institute for Respiratory Health, Edith Cowan University, Murdoch University, Queen Elizabeth II Medical Centre, Pathwest Laboratory Medicine, Monash University, Institut de Recherche en Cancérologie de Montpellier

Language: English

Topic: Occupational and environmental lung diseases

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,000

Funders: Australian Government, Simon Lee Foundation, Cancer Australia, University of Western Australia, National Health and Medical Research Council, Cancer Council Western Australia

Award: G3389004308

OpenAlex ID: W4200611702