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Team: Cholesterol Metabolism and therapeutic innovations, UMR 1037 INSERM-University of Toulouse, France

Key members: Marc Poirot (PI), Sandrine Silvente-Poirot (co-PI), Michel Record, Florence Dalenc, Frederic Courbon, Regis Soules.

Contacts:     Marc Poirot, marc.Poirot@Inserm.fr

                      Sandrine Silvente-Poirot, sandrine.poirot@inserm.fr

Research activities: We are studying cholesterol metabolism deregulations in cancers. We have discovered a metabolic pathway centered on 5,6-epoxycholesterols (EC) and controlled by the cholesterol-5,6-epoxide hydrolase (ChEH) which catalyzes the hydration of EC into cholestane-3β,5α,6β-triol (CT). EC exist as two diastereoisomeres α and β (αEC and βEC) that are differentially metabolized.  We found that αEC was metabolized into dendrogenin A (DDA) in healthy tissues. DDA results from the stereoselective condensation of αEC with a molecule of histamine. DDA is the first steroidal alkaloid ever identified in mammals and displays tumor suppressor properties through the modulation of LXRβ and the inhibition of the 3β-hydroxysteroid-Δ8,7-isomerase (D8D7I), a subunit of the ChEH. We found that DDA metabolism was deregulated in breast cancers (BC) in which a decrease in DDA levels was found compared to the normal breast (NB). The study of this deregulation led us to show that EC metabolism was different in BC and normal breast. Indeed,  the ChEH activity was upregulated in BC compared to NB and CT produced an oncometabolite, identified to be 6-oxo-cholestan-3β,5α-diol (OCDO). OCDO displays tumor promoter properties and is produced by an enzyme that we identified to be the 11β-hydroxysteroid dehydrogenase-type 2, the enzyme that inactivates the glucocorticoid cortisol into cortisone. We also showed that OCDO stimulated the proliferation of BC cells expressing or not the estrogen receptor through the modulation of the glucocorticoid receptor (GR).  Interestingly, we found that inhibition of OCDO production contributes to the antitumor activity of DDA in BC in vivo.

 Our data open new opportunities to detect and treat cancers that we are exploring.

 

Key papers related to ENOR:

Dendrogenin A drives LXR to trigger lethal autophagy in cancers.  Segala G, David M, de Medina P, Poirot MC, Serhan N,  Vergez F, Mougel A, Saland E, Carayon K,  Leignadier J, Caron N, Voisin M, Cherier J, Ligat L, Lopez F, Noguer E, Rives A, Payre B, al Saati T, Lamaziere A, Despres G, Lobaccaro JM, Baron S, Demur C, de Toni F, Larrue C, Boutzen H, Thomas F, Sarry JE, Record M, Récher C, Poirot M and Silvente-Poirot S. (2017) Nat commun, 8:1903

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor.Voisin M, de Medina P, Mallinger A, Dalenc F, Leignadier J, Serhan N, Soules R, Segala G, Huc-Claustre E, Mougel A, Noguer E, Mhamdi L, Bacquié E, Iuliano L, Zerbinati C, Lacroix-Triki M, Chaltiel L, Filleron T, Cavailles V, Al Saati T, Rochaix P, Duprez-Paumier R, Franchet C, Ligat L, Lopez F, Record M, Poirot M, Silvente-Poirot S. (2017) Proc Natl Acad Sci USA, 114(44) E9346–E9355

Dendrogenin A: a Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties.  Dalenc F, Poirot M & Silvente-Poirot S. (2015) Curr Med Chem, vol 22(30): 3533-3549

Cholesterol and cancer, In the balance, Silvente-Poirot S & Poirot M. (2014) Science, 343:1445-6

Discovery of Dendrogenin A: a new cholesterol metabolite that triggers antitumor activities. de Medina P, Paillasse M, Segala G, Voisin M, Mhamdi L, Morisseau C, Hammock B D, Filleron T, Dalenc F, Lacroix-Triki M, Pont F, Al Saati T, Silvente-Poirot S, Poirot M. (2013) Nature Commun. 4:1840

Cholesterol-5,6-epoxides. Chemistry, biochemistry, metabolic fate and cancer. Poirot M, Silvente-Poirot S.(2013) Biochimie, 95(3):622-31

Cholesterol metabolism and cancer: the good, the bad and the ugly. Silvente-Poirot S and Poirot M, (2012) Curr Opin Pharmacol. 12(6): 673-676

Cholesterol metabolism and resistance to tamoxifen. Poirot M, Silvente-Poirot S, Weichselbaum RR, (2012) Curr Opin Pharmacol. 12(6): 683-689

Cholesterol epoxide hydrolase and cancer Silvente-Poirot S, Poirot M, (2012), Curr Opin Pharmacol. 12(6): 696-703 (review) (Cover Art).

Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands. de Medina P, Paillasse M, Segala G, Poirot M, Silvente-Poirot S. (2010). Proc Natl Acad Sci U S A, 107(30):13520-5.