Abstract
Abstract From a clinical standpoint, epithelial ovarian cancer (EOC) metastasis is a significant cause of morbidity and mortality in patients. The signal transducer and activator of transcription-3 (STAT3) protein is a cytoplasmic transcription factor that mediates signals from cytokines and growth factors and non-growth factor tyrosine kinases. Constitutive activation of STAT3 is commonly observed in human ovarian cancer cell lines and primary tumors. In addition to well-established roles for STAT3 in cell proliferation and survival, evidence suggests it also plays a role in tumor cell migration and invasion. To determine the role of STAT3 in ovarian carcinoma cell migration and invasion, we used human ovarian carcinoma cell lines with enforced expression or RNA interference (RNAi)-mediated knockdown of STAT3. To determine the mechanism(s) of STAT3 activation in EOC cells, pharmacologic and RNAi approaches were used to interrogate candidate activators. Specifically, we show that expression of constitutively activated STAT3 results in increased MMP-2 expression and invasion of EOC cells. As Src is both a key mediator of tumor cell migration and invasion and an upstream activator of STAT3, we utilized pharmacologic and RNA interference (RNAi) approaches to determine if Src-mediated activation of STAT3 is essential for migration and invasion in ovarian carcinoma cells. Inhibition of either Src or STAT3 alone similarly diminishes migration of ovarian cancer cells. However, surprisingly, Src inhibition results in a concomitant increase in phosphorylation (activation) of STAT3, suggesting a compensatory mechanism for STAT3 activation. In support of this, simultaneous inhibition of STAT3 and Src results in significantly greater inhibition of migration. To uncover the alternative mechanism for STAT3 activation, we investigated the interactions of STAT3 with key proteins localized in focal adhesion complexes and known to mediate cell motility. This analysis showed that activated STAT3 co-localizes at focal adhesion complexes with phosphorylated focal adhesion kinase (FAK) and neural precursor cell expressed, developmentally downregulated 9 (NEDD9). In addition, using pharmacologic and RNAi-mediated approaches for candidate inhibition, we showed that focal complex localization of STAT3 is dependent on both FAK and NEDD9 and that transcriptional activation of STAT3 in ovarian carcinoma cells is dependent on FAK, rather than JAK2 or SRC. Taken together, these data suggest an important and previously unappreciated role for FAK in STAT3 activation, migration and invasion of ovarian carcinoma cells. These results also nominate FAK as a potential therapeutic target for ovarian cancer treatment. Citation Format: Fang Xiao, Denise C. Connolly. FAK mediates STAT3 activation, migration and invasion in ovarian carcinoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2014-2095
Published Version
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