β1 Integrin Adhesion Enhances IL-6–Mediated STAT3 Signaling in Myeloma Cells: Implications for Microenvironment Influence on Tumor Survival and Proliferation

Abstract

The bone marrow microenvironmental components interleukin (IL)-6 and fibronectin (FN) individually influence the proliferation and survival of multiple myeloma (MM) cells; however, in vivo, these effectors most likely work together. We examined signaling events, cell cycle progression, and levels of drug response in MM cells either adhered to FN via B1 integrins, stimulated with IL-6, or treated with the two combined. Although G 1 -S cell cycle arrest associated with FN adhesion was overcome when IL-6 was added, the cell adhesion-mediated drug resistance (CAM-DR) was maintained in the presence of IL-6. Concomitant exposure of MM cells to IL-6 and FN adhesion revealed a dramatic increase in signal transducers and activators of transcription 3 (STAT3) phosphorylation, nuclear translocation, and DNA binding, compared with either IL-6 or FN adhesion alone in four MM cell lines. Importantly, this increase in STAT3 activation correlated with a novel association between STAT3 and gp130 in cells adhered to FN before stimulation with IL-6, relative to nonadherent cells. Taken together, these results suggest a mechanism by which collaborative signaling by B1 integrin and gp130 confers an increased survival advantage to MM cells. [Cancer Res 2009;69(3):1009-15]

RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

“…Ser227 for the treatment of multiple myeloma IL-6-mediated cell protection is one of the major cell-extrinsic mechanisms for multidrug resistance in myeloma cells (5,32). While cell death induction by lenalidomide, the most powerful IMiD that has a direct cytotoxic effect on multiple myeloma cells (33) Fig.…”

S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer

“…Another explanation is based on the role of S100A7 in OSM-induced migration. In MCF7 and T47D cells, fibronectin is upregulated by OSM (Zhang et al, 2003) and, in multiple myeloma, can activate STAT3 in cooperation with IL-6 via b1 integrin signaling (Shain et al, 2009). If S100A7 mediates OSM-induced migration in MCF7 cells, it may also regulate STAT3 through integrin signaling.…”

Protective function of interleukin 27 in colitis-associated cancer via suppression of inflammatory cytokines in intestinal epithelial cells

“…CXCR2 C MDSCs is crucial to CAC model because CXCR2 ¡/¡ mice were observed with significantly reduced tumor formation. 27,49 We proved loss of WSX-1 upregulates the level of IL-6, TNF-a, GM-CSF and CXCL1 in IECs. IL-6 and TNF-a are not only acknowledged as pro-inflammatory cytokines, but also efficiently promote tumor cell proliferation, 32,33 which increase tumor formation in CAC mice.…”