Antiestrogen-binding site ligands induce autophagy in myeloma cells that proceeds through alteration of cholesterol metabolism
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Brigitte Sola1, Marc Poirot2,3,4, Philippe de Medina2,5, Sophie Bustany1, Véronique Marsaud6, Sandrine Silvente-Poirot2,3,4, and Jack-Michel Renoir7
1 Normandie Univ, UNICAEN EA4652, Caen, France
2 INSERM UMR1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France
3 Université de Toulouse III, Toulouse, France
4 Institut Claudius Regaud, Toulouse, France
5 Affichem, Toulouse, France
6 Institut Curie, CNRS UMR3347, INSERM U1021, Orsay, France
7 Institut Gustave Roussy, INSERM U749, Villejuif, France.
Jack-Michel Renoir, email:
Keywords: multiple myeloma, tamoxifen, autophagy, apoptosis, cholesterol metabolism
Received: May 30, 2013 Accepted: June 10, 2013 Published: June 11, 2013
Multiple myeloma (MM) is a malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Despite extensive efforts to design drugs targeting tumoral cells and their microenvironment, MM remains an incurable disease for which new therapeutic strategies are needed. We demonstrated here that antiestrogens (AEs) belonging to selective estrogen receptor modulators family induce a caspase-dependent apoptosis and trigger a protective autophagy. Autophagy was recognized by monodansylcadaverin staining, detection of autophagosomes by electronic microscopy, and detection of the cleaved form of the microtubule-associated protein light chain 3. Moreover, autophagy was inhibited by drugs such as bafilomycin A1 and 3-methyladenosine. Autophagy was mediated by the binding of AEs to a class of receptors called the antiestrogen binding site (AEBS) different from the classical estrogen nuclear receptors. The binding of specific ligands to the AEBS was accompanied by alteration of cholesterol metabolism and in particular accumulation of sterols: zymostenol or desmosterol depending on the ligand. This was due to the inhibition of the cholesterol-5,6-epoxide hydrolase activity borne by the AEBS. We further showed that the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway mediated autophagy signaling. Moreover, AEBS ligands restored sensitivity to dexamethasone in resistant MM cells. Since we showed previously that AEs arrest MM tumor growth in xenografted mice, we propose that AEBS ligands may have a potent antimyeloma activity alone or in combination with drugs used in clinic.
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