Antiestrogen-binding site ligands induce autophagy in myeloma cells that proceeds through alteration of cholesterol metabolism

Abstract

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.

Hexokinase II inhibitor, 3-BrPA induced autophagy by stimulating ROS formation in human breast cancer cells

“…Autophagy can prevent apoptosis [39], necrosis [40], and necroptosis [41]. We used z-VAD-fmk to rule out the contribution of pan-caspases in 3-BrPA plus CQ-induced cell death.…”

Deazaneplanocin A Is a Promising Drug to Kill Multiple Myeloma Cells in Their Niche

“…The identity of non-commercially obtained cells was checked as described before [19]. Multiple myeloma cell lines (MMCLs) were maintained in RPMI 1640 medium supplemented with 100 U/mL penicillin, 100 U/mL streptomycin, 2 mM L-glutamine (all from Lonza, Basel, Switzerland) and 10% fetal calf serum (FCS, PAA Lab., Villacoublay, France).…”

Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast

“…A high body mass index (BMI) correlates with increased risk for multiple myeloma [61,62], possibly through increased conversion of androgens to estrogens that in turn stimulate estrogen receptor positive multiple myeloma cells [63–65]. High BMI may also lead to increased multiple myeloma development through increases in inflammatory mediators or CCL2- and COX-2-driven pathways that stimulate tumor growth in the bone marrow [66] but more mechanistic studies are needed to understand these signals.…”