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

Experimental Therapeutics and Oncologic Sciences Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: William S. Dalton, Departments of Experimental Therapeutics and Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-745-4361; Fax: 813-745-4258; E-mail: Dalton{at}moffitt.usf.edu.

Key Words: adhesion • β1 integrin • IL-6 • STAT3 • multiple myeloma • microenvironment

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 β1 integrins, stimulated with IL-6, or treated with the two combined. Although G₁-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 β1 integrin and gp130 confers an increased survival advantage to MM cells. [Cancer Res 2009;69(3):1009–15]