Article

Hyaluronic Acid Induces Survival and Proliferation of Human Myeloma Cells through an Interleukin-6-mediated Pathway Involving the Phosphorylation of Retinoblastoma Protein

Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2001; 276(18):14728-36. DOI: 10.1074/jbc.M003965200
Source: PubMed

ABSTRACT

Originating from a post-switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant myeloma
cells accumulate in the bone marrow of patients with multiple myeloma. In this favorable microenvironment their growth and
survival are dependent upon both soluble factors and physical cell-to-cell and cell-to-extracellular matrix contacts. In this
report we show that hyaluronan (HA), a major nonprotein glycosaminoglycan component of the extracellular matrix in mammalian
bone marrow, is a survival and proliferation factor for human myeloma cells. The effect of HA is mainly mediated through a
gp 80-interleukin 6 (IL-6) receptor pathway by a CD44-independent mechanism, suggesting that HA retains and concentrates IL-6
close to its site of secretion, thus favoring its autocrine activity. In addition, we show that HA-mediated survival and proliferation
of myeloma cells is associated with a down-regulation in the expression of p27kip1 cyclin-dependent kinase inhibitor and a hyperphosphorylation of the retinoblastoma protein (pRb). These data suggest that
HA could be an important component in the myeloma cell physiopathology in vivo by potentiating autocrine and/or paracrine IL-6 activities.

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    • "Moreover, it was found that Pgp and CD44 coimmunoprecipitate and colocalize in the cell membrane (Miletti-Gonzá lez et al., 2005). Recent observations suggest a potential role for interactions of CD44 with its ligand HA in the survival and chemoresistance of hematopoietic malignant cells (Vincent et al., 2001, 2003). Our result of upregulated CD44 expression in K562/A02 is in agreement with these findings. "
    S Yan · D Ma · M Ji · D Guo · J Dai · P Zhao · C Ji
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    ABSTRACT: Drug resistance is the major setback of acute myeloid leukemia (AML) therapy. Notch proteins have demonstrated functional regulation in cell proliferation, differentiation, and apoptosis and thus may affect drug resistance. Our study aimed to identify the Notch-related gene profile in drug-resistant AML cells and provide potential strategies for resistant AML therapy. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was conducted to detect the cytotoxicity of adriamycin toward K562 and drug-resistant K562/A02. Intracellular mean fluorescence intensity was monitored to reflect the intake of adriamycin by confocal microscopy. cDNA microarray was used to test the expression of 113 Notch signaling pathway-related genes in K562/A02 and K562. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) and western blot were used to validate the results from microarray. K562/A02 cells showed a 65-fold higher IC(50) to adriamycin and less intracellular accumulation of adriamycin than K562. cDNA microarray showed marked increases in binding of collagen and cell proliferation-related genes (CD44, DLL3, IL17B, NUMB, and NUMBL) and decreases in signal transduction and transcription factor activity related genes (FZD9, GBP2, GLI1, GLI2, IFNG, KRT5, Notch2, and Notch3). The change of gene expression was further validated by real-time RT-PCR and western blot. Notch signaling pathway-related genes may contribute to the drug resistance of AML.
    Preview · Article · Apr 2009 · International journal of laboratory hematology
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    • "These cells communicate through a complex series of molecular pathways including adhesion molecules, cytokines, chemokines, growth factors and their respective receptors that may be critical for disease progression. Previous studies suggest that bone marrow stromal cells (BMSCs) in myeloma patients differ from those of healthy donors [1] [2] [3] [4] [8] [19] [20]. We reported elsewhere that BMSCs of multiple myeloma patients, in comparison to a control, produced more IL-6, IL-10, TNF-α, HGF, OPN and BAFF in response to RPMI8226 cells [21]. "
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    ABSTRACT: We examined cytokine production by bone marrow stromal cells (BMSCs) of patients with multiple myeloma (MM) in response to contact with myeloma RPMI8226 cells in standard 2-dimensional (2D) cultures and in 3-dimensional (3D) cultures on a gelatine sponge scaffold. It was detected that BMSCs in the 3D cultures produced more IL-11 and HGF and less IL-10 than in the 2D cultures. Moreover, RPMI8226 cells after contact with BMSCs in 3D cultures produced more sIL-6R than in the classic 2D cultures. We concluded that 3D cultures of BMSCs with myeloma cells offered a promising model for in vitro examination of interactions between myeloma cells and the bone marrow stroma and for examination of potent antimyeloma agents.
    Full-text · Article · Feb 2009 · Folia Histochemica et Cytobiologica
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    • "Such an effect could result, in vivo, in a diminished influence of paracrine factors on MM cell survival. It is tempting to speculate, on the basis of our data and our previous report (Vincent et al, 2001), that components of the bone marrow microenvironment , such as HA, could influence the emergence of drug-resistant tumour cells by making up for the diminution of paracrine factors by favouring autocrine growth factors or cytokine activities. The fact that HA induced IL-6- accumulation in the culture medium of the XG-1 cell line, without affecting IL-6 mRNA expression, strongly strengthens our hypothesis. "
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    ABSTRACT: Originating from a post-switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant multiple myeloma (MM) cells accumulate in the bone marrow of patients with MM. In this favourable microenvironment, their growth and survival are dependent upon both soluble factors and physical cell-to-cell and cell-to-extracellular-matrix contacts. In this study, hyaluronan (HA), a major non-protein glycosaminoglycan component of the extracellular matrix in mammalian bone marrow, acted as a survival factor against dexamethasone (Dex)-induced apoptosis in MM cell lines. These effects were mediated through an interleukin 6 (IL-6) autocrine pathway, involving signal transducers and activators of transcription-3 phosphorylation on IL-6-dependent XG-1 and XG-6 cell lines. HA promoted accumulation of IL-6 in the culture medium without affecting IL-6 gene expression, suggesting that HA protects, stabilizes and concentrates IL-6 close to its site of secretion, thus favouring its autocrine activity. In contrast, in the IL-6-independent RPMI8226 cell line, HA survival effect was mediated through a gp80-IL-6 receptor-independent pathway, resulting in the upregulation of Bcl-2 anti-apoptotic protein expression and nuclear factor-kappaB activation. Taken together, these data suggest that HA antagonizes Dex-induced apoptosis of MM cells by favouring the autocrine activity of different cytokines or growth factors. As HA is a major component of the bone marrow extracellular matrix, these findings support the idea that HA could play a major role in the survival of MM cells in vivo, and could explain why MM cells accumulate in the bone marrow of patients with MM and escape conventional chemotherapy.
    Full-text · Article · May 2003 · British Journal of Haematology
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