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.

Abstract

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.

• Authors: M Ogawa, T Nishiura, K Oritani, H Yoshida, M Yoshimura, Y Okajima, J Ishikawa, K Hashimoto, I Matsumura, Y Tomiyama, Y Matsuzawa
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 15 Pg. 4262-9 (Aug 01 2000) ISSN: 0008-5472 [Print] United States
• PMID: 10945640 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon Type I
• Interleukin-6
• Receptors, Interferon
• Receptors, Interleukin-6
• Recombinant Proteins
• Receptor, Interferon alpha-beta
• Insulin-Like Growth Factor I
• Dexamethasone
• Phosphatidylinositol 3-Kinases
• Receptor, IGF Type 1
• Mitogen-Activated Protein Kinase 1
• CASP3 protein, human
• Caspase 3
• Caspases

Topics

• Aged
• Apoptosis (drug effects, genetics)
• Caspase 3
• Caspases (metabolism)
• Dexamethasone (antagonists & inhibitors, toxicity)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Insulin-Like Growth Factor I (antagonists & inhibitors, biosynthesis, physiology)
• Interferon Type I (pharmacology)
• Interleukin-6 (pharmacology)
• MAP Kinase Signaling System (drug effects, physiology)
• Mitogen-Activated Protein Kinase 1 (metabolism, physiology)
• Multiple Myeloma (enzymology, pathology)
• Phosphatidylinositol 3-Kinases (metabolism, physiology)
• Receptor, IGF Type 1 (antagonists & inhibitors, physiology)
• Receptor, Interferon alpha-beta
• Receptors, Interferon (physiology)
• Receptors, Interleukin-6 (physiology)
• Recombinant Proteins (pharmacology)
• Signal Transduction (drug effects, physiology)
• Tumor Cells, Cultured (drug effects, pathology)