PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective
M. Lizeth Orozco Morales,
Catherine A. Rinaldi,
Emma de Jong,
Sally M. Lansley,
Joel P.A. Gummer,
Bence Olasz,
Shabarinath Nambiar,
Danika E. Hope,
Thomas H. Casey,
Y. C. Gary Lee,
Connull Leslie,
Gareth Nealon,
David M. Shackleford,
Andrew K. Powell,
Marina Grimaldi,
Patrick Balaguer,
Rachael M. Zemek,
Anthony Bosco,
Matthew J. Piggott,
Alice Vrielink,
Richard A. Lake,
W. Joost Lesterhuis
Affiliations
M. Lizeth Orozco Morales
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia
Catherine A. Rinaldi
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; Centre for Microscopy Characterisation and Analysis, Nedlands, WA 6009, Australia
Emma de Jong
Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia
Sally M. Lansley
Institute for Respiratory Health, Nedlands, WA 6009, Australia
Joel P.A. Gummer
School of Science, Department of Science, Edith Cowan University, Joondalup, WA 6027, Australia; UWA Medical School, The University of Western Australia, Crawley, WA 6009, Australia
Bence Olasz
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia
Shabarinath Nambiar
School of Veterinary and Life Science, Murdoch University, Murdoch, WA 6150, Australia
Danika E. Hope
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia
Thomas H. Casey
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia
Y. C. Gary Lee
Institute for Respiratory Health, Nedlands, WA 6009, Australia
Connull Leslie
Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia
Gareth Nealon
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia
David M. Shackleford
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Andrew K. Powell
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Marina Grimaldi
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34090, France
Patrick Balaguer
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34090, France
Rachael M. Zemek
Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia
Anthony Bosco
Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia
Matthew J. Piggott
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia
Alice Vrielink
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia
Richard A. Lake
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia
W. Joost Lesterhuis
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia; Corresponding author
Summary: 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.
