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 blood of a patient with advanced IgG-kappa 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 (alphaIGF-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-alpha as well as IL-6 prevented DEX plus alphaIGF-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-alpha blocked DEX plus alphaIGF-1R-induced apoptosis through activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways.
Ogawa
M
M
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Japan.
Nishiura
T
T
Oritani
K
K
Yoshida
H
H
Yoshimura
M
M
Okajima
Y
Y
Ishikawa
J
J
Hashimoto
K
K
Matsumura
I
I
Tomiyama
Y
Y
Matsuzawa
Y
Y
D000368:Aged; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D007370:Interferon Type I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D009101:Multiple Myeloma / Q000201:enzymology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology*
D007370:Interferon Type I; D015850:Interleukin-6; D017471:Receptors, Interferon; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D019950:Mitogen-Activated Protein Kinase 1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases