Persistent organic pollutants promote aggressiveness in prostate cancer
Julio Buñay
(1, 2, 3)
,
Myriam Kossai
(3, 4)
,
Christelle Damon-Soubeyrant
(1, 2, 3)
,
Angélique de Haze
(1, 2, 3)
,
Jean-Paul Saru
(1, 2, 3)
,
Amalia Trousson
(1, 2, 3)
,
Cyrille de Joussineau
(1, 2, 3)
,
Erwan Bouchareb
(3, 2, 1)
,
Ayhan Kocer
(3, 2, 1)
,
Marine Vialat
(3, 2, 1)
,
Sarah Dallel
(3, 2, 1, 5)
,
Françoise Degoul
(3, 2, 1)
,
Frédéric Bost
(6)
,
Stephan Clavel
(7)
,
Frédérique Penault-Llorca
(3, 4)
,
Marie-Pierre Valli
(8)
,
Laurent Guy
(8)
,
Jason Matthews
(9)
,
Yoan Renaud
(3, 1, 2)
,
Michael Ittmann
(10)
,
Jeffrey Jones
,
Laurent Morel
(1, 3, 2)
,
Jean-Marc Lobaccaro
(1, 3, 2)
,
Silvère Baron
(1, 3, 2)
1
GReD -
Génétique, Reproduction et Développement
2 CRNH A - Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand]
3 GCCA - Groupe Cancer Clermont Auvergne
4 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
5 Service Endocrinologie et Maladies Métaboliques [CHU Clermont-Ferrand]
6 C3M - Centre méditerranéen de médecine moléculaire
7 IPMC - Institut de pharmacologie moléculaire et cellulaire
8 Service Urologie [CHU Clermont-ferrand]
9 Institute of Basic Medical Sciences [Oslo]
10 Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, and Michael E. DeBakey VAMC Houston, Houston, TX, 77030, USA
2 CRNH A - Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand]
3 GCCA - Groupe Cancer Clermont Auvergne
4 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
5 Service Endocrinologie et Maladies Métaboliques [CHU Clermont-Ferrand]
6 C3M - Centre méditerranéen de médecine moléculaire
7 IPMC - Institut de pharmacologie moléculaire et cellulaire
8 Service Urologie [CHU Clermont-ferrand]
9 Institute of Basic Medical Sciences [Oslo]
10 Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, and Michael E. DeBakey VAMC Houston, Houston, TX, 77030, USA
Myriam Kossai
- Fonction : Auteur
- PersonId : 1276810
- ORCID : 0000-0002-1968-652X
Christelle Damon-Soubeyrant
- Fonction : Auteur
- PersonId : 1276811
- ORCID : 0009-0002-8126-240X
Marine Vialat
- Fonction : Auteur
- PersonId : 1218064
- ORCID : 0000-0001-7093-1175
Stephan Clavel
- Fonction : Auteur
- PersonId : 803737
- ORCID : 0000-0003-0484-3112
Frédérique Penault-Llorca
- Fonction : Auteur
- PersonId : 1188534
- ORCID : 0000-0002-4279-5492
- IdRef : 076501450
Yoan Renaud
- Fonction : Auteur
- PersonId : 765133
- ORCID : 0000-0002-4036-8315
- IdRef : 131388932
Michael Ittmann
- Fonction : Auteur
- PersonId : 1276812
- ORCID : 0000-0003-4802-0978
Jeffrey Jones
- Fonction : Auteur
Silvère Baron
- Fonction : Auteur
- PersonId : 171076
- IdHAL : silvere-baron
- ORCID : 0000-0002-4524-3087
- IdRef : 079823882
Résumé
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.