TY - JOUR
T1 - 5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of Tamoxifen in breast cancer cells
AU - Segala, Gregory
AU - De Medina, Philippe
AU - Iuliano, Luigi
AU - Zerbinati, Chiara
AU - Paillasse, Michael R.
AU - Noguer, Emmanuel
AU - Dalenc, Florence
AU - Payre, Bruno
AU - Jordan, V. Craig
AU - Record, Michel
AU - Silvente-Poirot, Sandrine
AU - Poirot, Marc
N1 - Funding Information:
We thank David J Mangelsdorf (University of Texas, Dallas, TX, USA) for kindly providing plasmids encoding human LXR and LXRE-luc. MP and SSP are supported by internal grants from the “Institut National de la Santé et de la Recherche Medicale”, the University of Toulouse III and an external grant from the “Fondation de France”. VCJ is supported by P30CA051008, SSP is in charge of research at the Centre National de la Recherche Scientifique. GS is funded by the “Ministere de la Recherche” and the “Association pour la Recherche sur le Cancer” .
PY - 2013
Y1 - 2013
N2 - Tamoxifen (Tam) is a selective estrogen receptor modulator (SERM) that remains one of the major drugs used in the hormonotherapy of breast cancer (BC). In addition to its SERM activity, we recently showed that the oxidative metabolism of cholesterol plays a role in its anticancer pharmacology. We established that these effects were not regulated by the ER but by the microsomal antiestrogen binding site/ cholesterol-5,6-epoxide hydrolase complex (AEBS/ChEH). The present study aimed to identify the oxysterols that are produced under Tam treatment and to define their mechanisms of action. Tam and PBPE (a selective AEBS/ChEH ligand) stimulated the production and the accumulation of 5,6a-epoxycholesterol (5,6a-EC), 5,6a-epoxy-cholesterol-3b- sulfate (5,6-ECS), 5,6b-epoxy-cholesterol (5,6b-EC) in MCF-7 cells through a ROS-dependent mechanism, by inhibiting ChEH and inducing sulfation of 5,6a-EC by SULT2B1b. We showed that only 5,6a-EC was responsible for the induction of triacylglycerol (TAG) biosynthesis by Tam and PBPE, through the modulation of the oxysterol receptor LXRb. The cytotoxicity mediated by Tam and PBPE was triggered by 5,6b-EC through an LXRb-independent route and by 5,6-ECS through an LXRb-dependent mechanism. The importance of SULT2B1b was confirmed by its ectopic expression in the SULT2B1b(-) MDA-MB-231 cells, which became sensitive to 5,6a-EC, Tam or PBPE at a comparable level to MCF-7 cells. This study established that 5,6-EC metabolites contribute to the anticancer pharmacology of Tam and highlights a novel signaling pathway that points to a rationale for re-sensitizing BC cells to Tam and AEBS/ChEH ligands.
AB - Tamoxifen (Tam) is a selective estrogen receptor modulator (SERM) that remains one of the major drugs used in the hormonotherapy of breast cancer (BC). In addition to its SERM activity, we recently showed that the oxidative metabolism of cholesterol plays a role in its anticancer pharmacology. We established that these effects were not regulated by the ER but by the microsomal antiestrogen binding site/ cholesterol-5,6-epoxide hydrolase complex (AEBS/ChEH). The present study aimed to identify the oxysterols that are produced under Tam treatment and to define their mechanisms of action. Tam and PBPE (a selective AEBS/ChEH ligand) stimulated the production and the accumulation of 5,6a-epoxycholesterol (5,6a-EC), 5,6a-epoxy-cholesterol-3b- sulfate (5,6-ECS), 5,6b-epoxy-cholesterol (5,6b-EC) in MCF-7 cells through a ROS-dependent mechanism, by inhibiting ChEH and inducing sulfation of 5,6a-EC by SULT2B1b. We showed that only 5,6a-EC was responsible for the induction of triacylglycerol (TAG) biosynthesis by Tam and PBPE, through the modulation of the oxysterol receptor LXRb. The cytotoxicity mediated by Tam and PBPE was triggered by 5,6b-EC through an LXRb-independent route and by 5,6-ECS through an LXRb-dependent mechanism. The importance of SULT2B1b was confirmed by its ectopic expression in the SULT2B1b(-) MDA-MB-231 cells, which became sensitive to 5,6a-EC, Tam or PBPE at a comparable level to MCF-7 cells. This study established that 5,6-EC metabolites contribute to the anticancer pharmacology of Tam and highlights a novel signaling pathway that points to a rationale for re-sensitizing BC cells to Tam and AEBS/ChEH ligands.
KW - AEBS
KW - Breast cancer
KW - ChEH
KW - Cholesterol epoxide
KW - Sulfation
UR - http://www.scopus.com/inward/record.url?scp=84884324369&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884324369&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2013.02.031
DO - 10.1016/j.bcp.2013.02.031
M3 - Article
C2 - 23500540
AN - SCOPUS:84884324369
SN - 0006-2952
VL - 86
SP - 175
EP - 189
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 1
ER -