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Received for publication October 31, 2005.
Revised February 23, 2006.
Accepted for publication February 23, 2006.
B inhibition and gene expression signature
As multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signalling 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 MTS reduction assay, cell cycle analysis and western blotting. Mobility shift assay, immunoprecipitation, ChIP 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 vincristin and arsenic trioxide. Moreover, raloxifene inhibited constitutive NF-
B activity in myeloma cells by removing p65 from its binding sites through ER
interaction with p65. Importantly, micro-array analysis showed that raloxifene treatment decreased the expression of known NF-B-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g. c-myc, mip-1, 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-B-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells offering the framework for future studies of SERMs therapy in multiple myeloma.
Key words:
Sex hormones, NFkappaB, Signaling network analyses, Regulation of gene expression, Mechanisms of cell killing/apoptosis, Transcription targets
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