Data from Functional Roles of <i>Src</i> and <i>Fgr</i> in Ovarian Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b><i>Src</i> is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of <i>Src</i> silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of <i>Src</i> activity.</p><p><b>Experimental Design:</b> Cell viability after either <i>Src</i> or <i>Fgr</i> silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after <i>Src</i> silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of <i>in vivo Src</i> and/or <i>Fgr</i> silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues.</p><p><b>Results:</b><i>Src</i> silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, <i>Src</i> silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, <i>P</i> = 0.017; 84.3% reduction in HeyA8, <i>P</i> < 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of <i>Src</i> silencing on other SFK members in ovarian cancer cell lines. <i>Src</i> silencing resulted in significantly increased Fgr levels. Dual <i>Src</i> and <i>Fgr</i> silencing <i>in vitro</i> resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of <i>Src</i> and <i>Fgr in vivo</i> using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either <i>Src</i> or <i>Fgr</i> alone in the HeyA8 model (68.8%, <i>P</i> < 0.05).</p><p><b>Conclusions:</b> This study demonstrates that, in addition to <i>Src</i>, <i>Fgr</i> plays a biologically significant role in ovarian cancer growth and might represent an important target. <i>Clin Cancer Res; 17(7); 1713–21. ©2011 AACR</i>.</p></div>