Gonadotropin-releasing hormone promotes motility and invasiveness of ovarian cancer cells through transactivation of the insulin-like growth factor-1 receptor

Abstract

Ovarian cancer is the most lethal gynecological cancer with a dismal 5-year survival. This is because most ovarian cancer patients are diagnosed with already widespread metastasis and ascites, in which current therapies are ineffective. Gonadotropin-releasing hormone (GnRH) receptor is expressed in 80% of ovarian cancer. In addition to its well documented role in cell proliferation, our recent findings show an expanded role of GnRH in other aspects of ovarian tumor progression, such as cell migration and invasion. Here we report that these actions of GnRH were dependent on transactivation of the insulin-like growthfactor-1 (IGF-1) receptor. GnRH-induced migratory/invasive phenotypes were abolished by inhibition of the IGF-1 receptor, but not other receptor tyrosine kinases. GnRH significantly increased tyrosine phosphorylation of the IGF-1 receptor. Knocking down GnRH receptor by small interfering RNA was able to inhibit GnRH-induced IGF-1 receptor activation. Importantly, this transactivation caused rapid phosphorylation of the p120 catenin (p120ctn), which promoted translocation of p120ctn from membrane to cytosol and the subsequent activation of Rho GTPases Rac1 and Cdc42. RNA interference-mediated knockdown of p120ctn suppressed GnRH-stimulated migration and invasion of ovarian cancer cells, confirming that the effect was p120ctn specific. Expression of dominant negative mutants of Rac1 and Cdc42 also greatly reduced GnRH-mediated migration and invasion. These results show a novel crosstalk between GnRH and IGF-1 receptors in the proinvasive activity of GnRH in ovarian cancer cells and suggest potential benefits in the cotargeting of these pathways (This work is supported by Hong Kong Research Grants Council Grant HKU778108 to A.S.T.W.).