Abstract
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells with an enhanced proliferation and survival capacity within the bone marrow. Myeloma cells often develop drug resistance leading to treatment failure in the patients. Survivin is a member of the inhibitors of apoptosis (IAP) gene family that has been implicated in both cell viability and cell cycle regulation and described as overexpressed in most cancers. We have observed that survivin is expressed in human myeloma cell lines (HMCL) from moderate level in both HMCL XG-6 and MM1S to strong level in U266. Survivin was also detectable in primary myeloma cells. Moreover, survivin expression peaked at G2/M phase and was induced by IL-6 and IGF-1 through JAK/STAT and PI3K/AKT signalling pathways. In order to elucidate the role of survivin in myeloma cells, MM1S and XG-6 HMCL were transfected with human survivin cDNA. First, The survivin transient transfectants MM1S were significantly less sensitive to different drugs (dexamethasone, melphalan, paclitaxel, vincristine, doxorubicin) than the control vector transfectants MM1S. Secondly survivin stable transfected clones established from the HMCL XG-6 that is dependent on IL-6 for its growth, could be maintained in culture without IL-6 longer than control stable clones. Moreover these survivin clones proliferated without exogenous IL-6 in contrast to control clones that kept their IL-6 dependent growth. Furthermore, in vivo preliminary data suggest that survivin overexpressing clones could develop tumor in the SCID-human MM model in contrast to control clones. These data tend to prove that survivin participates in drug sensitivity, escape from IL-6 dependence and tumor formation capacity of HMCL. In summary, our findings suggest that survivin plays an important role in the pathogenesis of MM. A more defined understanding of survivin biology should enhance the rational development of drugs to inhibit its function in myeloma cells.
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