Raloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature.
Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-kappaB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma.
Olivier
Sabine
S
Department of Rheumatology, Center for Biomedical Integrative Genoproteomics, University of Liège, Centre Hospitalier Universitaire Sart-Tilman, Belgium.
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Pierre
P
Castermans
Emilie
E
de Leval
Laurence
L
Tabruyn
Sebastien
S
Chariot
Alain
A
Malaise
Michel
M
Merville
Marie-Paule
MP
Bours
Vincent
V
Franchimont
Nathalie
N
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009101:Multiple Myeloma; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016328:NF-kappa B; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride