Increasing evidence points towards a causal link between exposure to persistent organic pollutants (POPs) with increased incidence and aggressivity of various cancers. Among these POPs, dioxin and PCB-153 are widely found in our environment and represent a significant source of contamination. Dioxin exposure has already been linked to cancer such as non-Hodgkin's lymphoma, but remains to be more extensively investigated in other cancers. Potential implications of dioxin and PCB-153 in prostate cancer progression spurred us to challenge both ex vivo and in vivo models with low doses of these POPs. We found that dioxin or PCB-153 exposure increased hallmarks of growth and metastasis of prostate cancer cells ex vivo and in grafted NOD-SCID mice. Exposure induced histopathological carcinoma-like patterns in the Ptenpc-/- mice. We identified up-regulation of Acetyl-CoA Acetyltransferase-1 (ACAT1) involved in ketone bodies pathway as a potential target. Mechanistically, genetic inhibition confirmed that ACAT1 mediated dioxin effect on cell migration. Using public prostate cancer datasets, we confirmed the deregulation of ACAT1 and associated gene encoded ketone bodies pathway enzymes such as OXCT1, BDH1 and HMGCL in advanced prostate cancer. To further explore this link between dioxin and ACAT1 deregulation, we analyzed a unique prostate-tumour tissue collection from the USA veterans exposed to agent orange, known to be highly contaminated by dioxin because of industrial production. We found that ACAT1 histoscore is significantly increased in exposed patients. Our studies reveal the implication of dioxin and PCB-153 to induce a prometastatic programme in prostate tumours and identify ACAT1 deregulation as a key event in this process.
Oncogene. 2023 Aug 17 [Epub ahead of print]
Julio Buñay, Myriam Kossai, Christelle Damon-Soubeyrant, Angélique De Haze, Jean-Paul Saru, Amalia Trousson, Cyrille de Joussineau, Erwan Bouchareb, Ayhan Kocer, Marine Vialat, Sarah Dallel, Françoise Degoul, Frédéric Bost, Stephan Clavel, Frédérique Penault-Llorca, Marie-Pierre Valli, Laurent Guy, Jason Matthews, Yoan Renaud, Michael Ittmann, Jeffrey Jones, Laurent Morel, Jean-Marc Lobaccaro, Silvère Baron
Université Clermont Auvergne, iGReD, CNRS UMR 6293, INSERM U1103, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France., Groupe Cancer Clermont Auvergne, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France., Université Côte d'Azur, INSERM U1065, C3M, Equipe Labellisée Ligue Nationale contre le Cancer, 2022, F-06204, Nice, France., Université Côte d'Azur, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, Sophia-Antipolis, Valbonne, France., Service d'Urologie, CHU Clermont-Ferrand, UMR1240 INSERM, Université Clermont-Auvergne, Clermont Ferrand, France., Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Université Clermont Auvergne, iGReD, CNRS UMR 6293, INSERM U1103, 28, place Henri Dunant, BP38, 63001, Clermont-Ferrand, France. .