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 5,6 alpha-epoxy-cholesterol (5,6 alpha-EC), 5,6 alpha-epoxy-cholesterol-3 beta-sulfate (5,6-ECS), 5,6 beta-epoxy-cholesterol (5,6 beta-EC) in MCF-7 cells through a ROS-dependent mechanism, by inhibiting ChEH and inducing sulfation of 5,6 alpha-EC by SULT2B1b. We showed that only 5,6 alpha-EC was responsible for the induction of triacylglycerol (TAG) biosynthesis by Tam and PBPE, through the modulation of the oxysterol receptor LXR beta. The cytotoxicity mediated by Tam and PBPE was triggered by 5,6 beta-EC through an LXR beta-independent route and by 5,6-ECS through an LXR beta-dependent mechanism. The importance of SULT2B1b was confirmed by its ectopic expression in the SULT2B1b(-) MDA-MB-231 cells, which became sensitive to 5,6 alpha-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. (C) 2013 Elsevier Inc. All rights reserved.
5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of Tamoxifen in breast cancer cells / Gregory, Segala; P. D., Medina; P., De Medina; D. E., Philippe Medina; Iuliano, Luigi; Zerbinati, Chiara; Michael R., Paillasse; Emmanuel, Noguer; Florence, Dalenc; Bruno, Payre; V., Craig Jordan; Michel, Record; Sandrine Silvente, Poirot; Marc, Poirot. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 86:1(2013), pp. 175-189. [10.1016/j.bcp.2013.02.031]
5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of Tamoxifen in breast cancer cells
IULIANO, Luigi;ZERBINATI, CHIARA;
2013
Abstract
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 5,6 alpha-epoxy-cholesterol (5,6 alpha-EC), 5,6 alpha-epoxy-cholesterol-3 beta-sulfate (5,6-ECS), 5,6 beta-epoxy-cholesterol (5,6 beta-EC) in MCF-7 cells through a ROS-dependent mechanism, by inhibiting ChEH and inducing sulfation of 5,6 alpha-EC by SULT2B1b. We showed that only 5,6 alpha-EC was responsible for the induction of triacylglycerol (TAG) biosynthesis by Tam and PBPE, through the modulation of the oxysterol receptor LXR beta. The cytotoxicity mediated by Tam and PBPE was triggered by 5,6 beta-EC through an LXR beta-independent route and by 5,6-ECS through an LXR beta-dependent mechanism. The importance of SULT2B1b was confirmed by its ectopic expression in the SULT2B1b(-) MDA-MB-231 cells, which became sensitive to 5,6 alpha-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. (C) 2013 Elsevier Inc. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
