title: Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma.
abstract: Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoid-induced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex induced apoptosis while triggering an imbalance between anti- and pro-apoptotic Bcl-2 proteins. Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects.
authors: Myelomax, Nantes, France.|CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France.
authors: Charlotte
authors: C
authors: Kervoëlen
authors: Myelomax, Nantes, France.
authors: Emmanuelle
authors: E
authors: Ménoret
authors: CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France.|Hematology Clinic, University Hospital, Nantes, France.
authors: Patricia
authors: P
authors: Gomez-Bougie
authors: CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France.
authors: Régis
authors: R
authors: Bataille
authors: Hematology Laboratory, University Hospital, Nantes, France.
authors: Catherine
authors: C
authors: Godon
authors: Plate-forme in vivo, Cancéropôle Grand Ouest, Nantes, France.
authors: Séverine
authors: S
authors: Marionneau-Lambot
authors: CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France.|Hematology Clinic, University Hospital, Nantes, France.
authors: Philippe
authors: P
authors: Moreau
authors: CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France.|Hematology Clinic, University Hospital, Nantes, France.
authors: Catherine
authors: C
authors: Pellat-Deceunynck
authors: CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France.|Hematology Clinic, University Hospital, Nantes, France.
authors: Martine
authors: M
authors: Amiot
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis; D016923:Cell Death; D019938:Cyclin D1 / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000737:chemistry; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; C530104:CCND1 protein, human; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D019938:Cyclin D1; D003907:Dexamethasone
keywords: Bim; GILZ; glucocorticoid; glucocorticoid receptor; multiple myeloma