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

¹ Experimental Therapeutics and Oncologic Sciences Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

^* To whom correspondence should be addressed. E-mail: Dalton{at}moffitt.usf.edu.

	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 1 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 1 integrin and gp130 confers an increased survival advantage to MM cells. [Cancer Res 2009;69(3):1009–15]

Key Words: adhesion, 1 integrin, IL-6, STAT3, multiple myeloma, microenvironment