title: Ligands of the antiestrogen-binding site induce active cell death and autophagy in human breast cancer cells through the modulation of cholesterol metabolism.
abstract: We have recently reported that cytostatic concentrations of the microsomal antiestrogen-binding site (AEBS) ligands, such as PBPE (N-pyrrolidino-(phenylmethyphenoxy)-ethanamine,HCl) and tamoxifen, induced differentiation characteristics in breast cancer cells through the accumulation of post-lanosterol intermediates of cholesterol biosynthesis. We show here that exposure of MCF-7 (human breast adenocarcinoma cell line) cells to higher concentrations of AEBS ligands triggered active cell death and macroautophagy. Apoptosis was characterized by Annexin V binding, chromatin condensation, DNA laddering and disruption of the mitochondrial functions. We determined that cell death was sterol- and reactive oxygen species-dependent and was prevented by the antioxidant vitamin E. Macroautophagy was characterized by the accumulation of autophagic vacuoles, an increase in the expression of Beclin-1 and the stimulation of autophagic flux. We established that macroautophagy was sterol- and Beclin-1-dependent and was associated with cell survival rather than with cytotoxicity, as blockage of macroautophagy sensitized cells to AEBS ligands. These results show that the accumulation of sterols by AEBS ligands in MCF-7 cells induces apoptosis and macroautophagy. Collectively, these data support a therapeutic potential for selective AEBS ligands in breast cancer management and shows a mechanism that explains the induction of autophagy in MCF-7 cells by tamoxifen and other selective estrogen receptor modulators.
authors.affiliation: INSERM U563, Toulouse, France.
authors.forename: P
authors.initials: P
authors.lastname: de Medina
authors.forename: B
authors.initials: B
authors.lastname: Payré
authors.forename: N
authors.initials: N
authors.lastname: Boubekeur
authors.forename: J
authors.initials: J
authors.lastname: Bertrand-Michel
authors.forename: F
authors.initials: F
authors.lastname: Tercé
authors.forename: S
authors.initials: S
authors.lastname: Silvente-Poirot
authors.forename: M
authors.initials: M
authors.lastname: Poirot
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism*; D002454:Cell Differentiation; D002784:Cholesterol / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005021:Ethylamines / Q000633:toxicity*; D005260:Female; D006801:Humans; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects; D011759:Pyrrolidines / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D005021:Ethylamines; D008024:Ligands; C545696:N-pyrrolidino-(phenylmethyphenoxy)-ethanamine; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D014810:Vitamin E; D002784:Cholesterol