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Cytokines Prevent Dexamethasone-induced Apoptosis via the Activation of Mitogen-activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways in a New Multiple Myeloma Cell Line¹

Department of Internal Medicine and Molecular Science, Graduate School of Medicine B5 [M. O., T. N., K. O., H. Y., M. Y., Y. O., J. I., K. H., Y. T., Y. M.], and Department of Hematology and Oncology [I. M.], Osaka University, Suita, Osaka 565-0871, Japan

A new human myeloma cell line, OPM-6, was established from the peripheral blood of a patient with advanced IgG- plasma cell leukemia. Cytogenetic and phenotypic analysis confirmed that the cells were derived from the patient’s leukemic cells. Insulin-like growth factor-1 (IGF-1) acts as an autocrine growth factor in these cells. In addition, OPM-6 cells were particularly sensitive to dexamethasone (DEX), when endogenous IGF-1 was blocked. Under these conditions, >95% of the DEX-treated cells died within 36 h. Therefore, OPM-6 represents a potentially powerful tool for the analysis of the molecular mechanisms of DEX-induced apoptosis, because it is possible to easily analyze the direct effects of DEX using this system. Using this culture system of OPM-6, we demonstrated that the treatment with DEX plus a monoclonal antibody to the human IGF-1 receptor (IGF-1R) leads to the down-regulation of the gene expression of Bcl-xL, an antiapoptotic gene, and the activation of CPP32 during this apoptotic process. IFN- as well as IL-6 prevented DEX plus IGF-1R-induced apoptosis, and this prevention was blocked by the mitogen-activated protein kinase kinase inhibitor, PD098059, or the phosphatidylinositol 3-kinase inhibitor, wortmannin. Therefore, both IL-6 and IFN- blocked DEX plus IGF-1R-induced apoptosis through activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways.

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