Autocrine and paracrine interactions between multiple myeloma cells and bone marrow stromal cells by growth arrest-specific gene 6 crosstalk with interleukin-6 [Signal Transduction]

The pathogenesis of multiple myeloma (MM) has not yet been fully elucidated. Our microarray analysis and immunohistochemistry revealed significant upregulation of growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein with a structural homology with protein S, in bone marrow (BM) cells of MM patients. ELISA showed that the serum levels of soluble Gas6 were significantly increased in the MM patients when compared with healthy controls. Gas6 was overexpressed in the human CD138-positive MM cell line RPMI-8226. Exogenous Gas6 suppressed apoptosis induced by serum deprivation, and enhanced cell proliferation of the MM cells. The conditional media from the human BM stromal cell line HS-5 induced cell proliferation and anti-apoptosis of the MM cells with extracellular signal-regulated kinase, Akt, and nuclear factor-κB phosphorylation, which were reversed by the neutralizing antibody to Gas6 or interleukin-6 (IL-6). The expression of the TAM-family receptor Mer, which has been identified as a Gas6 receptor, was overexpressed in BM cells of MM patients. The knockdown of Mer by siRNA inhibited cell proliferation, anti-apoptosis and upregulation of intercellular cell adhesion molecule-1 (ICAM-1) in MM cells stimulated by a HS-5 cell-conditioned media. Furthermore, the Gas6 neutralizing antibody reduced the upregulation of IL-6 and ICAM-1 induced by a HS-5 cell-conditioned media in MM cells. The present study provides new evidence that autocrine and paracrine stimulation of Gas6 in concert with IL-6 contributes to the pathogenesis of MM, suggesting that Gas6-Mer related signaling pathways may be a promising novel target for treating MM.

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