Cytokines prevent dexamethasone-induced apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in a new multiple myeloma cell line

A new human myeloma cell line, OPM-6, was established from the peripheral b lood of a patient with advanced IgG-kappa plasma cell leukemia. Cytogenetic and phenotypic analysis confirmed that the cells were derived from the pat ient's Leukemic cells. Insulin-like growth factor-1 (IGF-1) acts as an auto crine growth factor in these cells. In addition, OPM-6 cells were particula rly sensitive to dexamethasone (DEX), when endogenous IGF-1 was blocked. Un der these conditions, >95% of the DEX-treated cells died within 36 h. There fore, OPM-6 represents a potentially powerful tool for the analysis of the molecular mechanisms of DEX-induced apoptosis, because it is possible to ea sily analyze the direct effects of DEX using this system. Using this cultur e system of OPM-6, we demonstrated that the treatment with DEX plus a monoc lonal antibody to the human IGF-1 receptor (alpha IGF-1R) leads to the down -regulation of the gene expression of Bcl-xL, an antiapoptotic gene, and th e activation of CPP32 during this apoptotic process. IFN-alpha as well as I L-6 prevented DEX plus alpha IGF-1R-induced apoptosis, and this prevention was blocked by the mitogen-activated protein kinase kinase inhibitor, PD098 059, or the phosphatidylinositol 3-kinase inhibitor, wortmannin. Therefore, both IL-6 and IFN-alpha blocked DEX plus alpha IGF-1R-induced apoptosis th rough activation of the mitogen-activated protein kinase and phosphatidylin ositol 3-kinase pathways.