Role for interleukin-6 and insulin-like growth factor-I via PI3-K/Akt pathway in the proliferation of CD56− and CD56+ multiple myeloma cells

Objectives Several studies including ours have suggested that lack of CD56 in multiple myeloma (MM) defines a unique patient subset with poorer prognosis. However, the mechanism underlying this aggressive behavior of CD56− MM has not been well elucidated. Interleukin-6 (IL-6) or insulin-like growth factor I (IGF-I) induce proliferation of MM cells. In this study, we report about the relationship between CD56 expression and responsiveness to these cytokines. Methods We sorted out both CD56− and CD56+ fractions from MM cell lines such as KMS-21-BM and U-266, and investigated their different responsiveness to IL-6 or IGF-I. Furthermore, we compared the effects of these cytokines on the regulation of cell-cycle distribution between CD56− and CD56+ cells. Results Although CD56− cells in both KMS-21-BM and U-266 cells responded significantly to IL-6, CD56+ cells did not. Ki-67+ cells in the CD56− cells were significantly increased by IL-6. Western blotting showed that IL-6 phosphorylated Akt, and upregulated and downregulated the level of cyclin D1 and p27 protein in the CD56− KMS-21-BM cells, respectively. LY-294002 completely blocked these effects of IL-6. On the other hand, Ki-67+ cells in the CD56+ cells did not respond to IL-6. Anti-IGF-I mAb significantly reduced Ki-67+ cells only in the CD56+ cells. IGF-I phosphorylated Akt and upregulated cyclin D1 in the CD56+ KMS-21-BM cells, which was completely blocked by LY294002. Conclusions These results suggest that CD56− and CD56+ MM cells could be stimulated by IL-6 and IGF-I, respectively, via PI3-K/Akt pathway, and provide useful information for anticytokine therapies.