Proliferation Of Myeloma Cell Lines Research Articles

Requirements of src family kinase activity associated with CD45 for myeloma cell proliferation by interleukin-6

AbstractSpecific intracellular signals mediated by interleukin-6 (IL-6) receptor complexes, such as signal transducer and activator of transcription 3 (STAT 3) and extracellular signal–regulated kinase (ERK) 1/2, are considered to be responsible for inducing a variety of cellular responses. In multiple myeloma, IL-6 only enhanced the proliferation of CD45+ tumor cells that harbored the IL-6–independent activation of src family kinases even though STAT3 and ERK1/2 could be activated in response to IL-6 in both CD45+ and CD45− cells. Furthermore, the IL-6–induced proliferation of CD45+ U266 myeloma cells was significantly suppressed by Lyn-specific antisense oligodeoxynucleotides or a selective src kinase inhibitor. These results indicate that the activation of both STAT3 and ERK1/2 is not enough for IL-6–induced proliferation of myeloma cell lines that require src family kinase activation independent of IL-6 stimulation. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cell lines by IL-6. We propose a mechanism for IL-6–induced cell proliferation that is strictly dependent upon the cellular context in myelomas.

The induction of apoptosis by a combined 1,25(OH)2D3 analog, EB1089 and TGF-β1 in NCI-H929 multiple myeloma cells

Previously, we reported that EB1089 inhibited the growth of NCI-H929 myeloma cells via cell cycle arrest and apoptosis. In the present study, we investigated whether a combined EB1089 and TGF-beta1 synergistically inhibited the cell proliferation of myeloma cell lines. While TGF-beta1 alone could not inhibit the proliferation of any of the tested myeloma cells, synergistic effect between EB1089 (1 x 10(-8) M) and TGF-beta1 (1 ng/ml) was observed in NCI-H929 cells. TGF-beta1 intensified the decreased expression of CDK2, CDK4, CDK6 and cyclin D1 in EB1089-treated NCI-H929 cells. However, these effects did not intensify to decrease CDK2 activity of EB1089-treated NCI-H929 cells, resulting in no difference in the extent of G1 arrest between EB1089- and both agents-treated cells. Remarkably, both agents synergistically induce apoptosis of NCI-H929 cells, which was accompanied with up-regulation of Bax, degradation of PARP and Rb proteins, and loss of mitochondrial transmembrane potential (deltapsim). EB1089 caused the induction of SMAD4, a mediator of TGF-beta1 signaling. In addition, a combined EB1089 and TGF-beta1 increased p21 and JNK/SAPK activity whereas neither EB1089 nor TGF-beta1 affected p21 and JNK/SAPK activity. Taken together, these results suggest that treatment with both EB1089 and TGF-beta1 synergistically inhibits the proliferation of NCI-H929 cells through apoptosis.

Characterization of Wue-1, a novel monoclonal antibody that stimulates the growth of plasmacytoma cell lines.

A new monoclonal antibody, Wue-1, which specifically recognizes normal and malignant plasma cells, is characterized. Biochemical studies showed that monoclonal antibodies (mAbs) recognize a protein of 94 kDa. Using triple-staining flow cytometry and double-labeling immunohistochemical techniques, two populations of plasma cells, i.e. lymphoplasmocytoid plasma cells located in the germinal center of lymphoid organs and reticular plasma cells at the paracortex or medullary cords of secondary lymphoid tissues, were distinguished. Wue-1 is expressed when B-cell markers become lost and secretory activity with plasma cell morphology appears. Cell surface markers were identified on normal plasma cells and compared with their malignant counterpart in vivo. Terminal plasma-cellular differentiation of malignant low- and high-grade B-cell lymphoma and anaplastic plasmacytoma, otherwise difficult to identify with conventional B-cell markers on tissue sections or fluorescence-activated cell sorter analyses, were detectable by Wue-1. In cell culture, Wue-1 enhanced the proliferation of myeloma cell lines but not normal plasma cells in a dose-dependent manner. Since Wue-1-induced proliferation was increased by interleukin (IL)-6, Wue-1 recognizes a so far unidentified antigen with functional properties. Therefore, Wue-1 represents a useful new tool for therapy and for the in vivo and in vitro studying of B-cell lymphomas and the mechanisms of B-cell differentiation.

Update of gp130 cytokines in multiple myeloma.

Interleukin (IL)-6 plays a major role in the control of the survival and proliferation of myeloma cell lines and primary myeloma cells. The genes of the receptors of IL-6 have been cloned, and the major signaling pathways involved in gp130 IL-6 transducer activation have been identified. In addition, another five cytokines that activate the gp130 IL-6 transducer have been identified. We review the recent data on gp130 cytokines and gp130-mediated signal transduction, their involvement in myeloma cell biology, and we discuss the possible therapeutic applications of this knowledge.