Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma - Centre de recherche en cancérologie Nantes-Angers Unité Mixte de Recherche 892 Inserm - 6299 CNRS Accéder directement au contenu
Article Dans Une Revue Oncotarget Année : 2015

Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma

Résumé

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.

Domaines

Cancer

Dates et versions

inserm-01817581 , version 1 (18-06-2018)

Identifiants

Citer

Charlotte Kervoëlen, Emmanuelle Ménoret, Patricia Gomez-Bougie, Régis Bataille, Catherine Godon, et al.. Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma. Oncotarget, 2015, 6 (29), ⟨10.18632/oncotarget.4616⟩. ⟨inserm-01817581⟩
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