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

M.L. Orozco Morales; C.A. Rinaldi; E. de Jong; S.M. Lansley; J.P.A. Gummer; B. Olasz; S. Nambiar; D.E. Hope; T.H. Casey; Y.C.G. Lee; C. Leslie; G. Nealon; D.M. Shackleford; A.K. Powell; M. Grimaldi; P. Balaguer; R.M. Zemek; A. Bosco; M.J. Piggott; A. Vrielink; R.A. Lake; W.J. Lesterhuis

doi:10.1016/j.isci.2021.103571

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

Journal article

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

M.L. Orozco Morales, C.A. Rinaldi, E. de Jong, S.M. Lansley, J.P.A. Gummer, B. Olasz, S. Nambiar, D.E. Hope, T.H. Casey, Y.C.G. Lee, …

iScience, Vol.25(1), Art. 103571

2021

DOI: https://doi.org/10.1016/j.isci.2021.103571

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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 tumours 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 antitumour effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

Details

Title: PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective
Authors/Creators: M.L. Orozco Morales (Author/Creator)
C.A. Rinaldi (Author/Creator)
E. de Jong (Author/Creator)
S.M. Lansley (Author/Creator)
J.P.A. Gummer (Author/Creator)
B. Olasz (Author/Creator)
S. Nambiar (Author/Creator)
D.E. Hope (Author/Creator)
T.H. Casey (Author/Creator)
Y.C.G. Lee (Author/Creator)
C. Leslie (Author/Creator)
G. Nealon (Author/Creator)
D.M. Shackleford (Author/Creator)
A.K. Powell (Author/Creator)
M. Grimaldi (Author/Creator)
P. Balaguer (Author/Creator)
R.M. Zemek (Author/Creator)
A. Bosco (Author/Creator)
M.J. Piggott (Author/Creator)
A. Vrielink (Author/Creator)
R.A. Lake (Author/Creator)
W.J. Lesterhuis (Author/Creator)
Publication Details: iScience, Vol.25(1), Art. 103571
Publisher: Elsevier
Identifiers: 991005541505907891
Copyright: © 2021 The Authors.
Murdoch Affiliation: School of Veterinary and Life Sciences
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.141 Hormone Therapy; 1.141.407 Nuclear Receptors
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine