Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma
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Charlotte Kervoëlen1,2, Emmanuelle Ménoret1, Patricia Gomez-Bougie2,3, Régis Bataille2, Catherine Godon4, Séverine Marionneau-Lambot5, Philippe Moreau2,3, Catherine Pellat-Deceunynck2,3, Martine Amiot2,3
1Myelomax, Nantes, France
2CRCNA, University of Nantes, INSERM, UMR892, CNRS, UMR 6299, Nantes, France
3Hematology Clinic, University Hospital, Nantes, France
4Hematology Laboratory, University Hospital, Nantes, France
5Plate-forme in vivo, Cancéropôle Grand Ouest, Nantes, France
Martine Amiot, e-mail: [email protected]
Keywords: multiple myeloma, glucocorticoid, glucocorticoid receptor, GILZ, Bim
Received: March 27, 2015 Accepted: July 06, 2015 Published: July 16, 2015
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.
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