Gonadotropin-releasing hormone (GnRH)-I and GnRH-II induce cell growth inhibition in human endometrial cancer cells: Involvement of integrin beta3 and focal adhesion kinase

Endometrial carcinoma is the most common neoplasm of the female genital tract, accounting for nearly one half of all gynecologic cancers in the Western world. It is estimated that approximately 40,000 new cases of endometrial cancer are diagnosed annually in the United States and about 7,000 women die of this disease, indicating that endometrial carcinoma is thus the fourth most common malignancy and the eighth leading cause of cancer-related death in women [1]. Although intensive research on pathological phenomena of endometrial cancer is currently going on, but exact cause and biological aspects of this disease are not well elucidated yet.Gonadotropin-releasing hormone (GnRH) is the hypothalamic hormone that mediates reproductive competence [2,3]. An intermittent GnRH secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition to reproductive roles of GnRH in hypo-pituitary ovarian (HPO) axis, GnRH-I, a classical form of GnRH, has an inhibitory effect on cell growth in human mammary, ovarian, endometrial, and prostate tumors and has been implicated as an antiproliferative factor of gynecologic cancers [4-8]. In particular, the agonistic or antagonistic analogs (or both) of GnRHs have been shown to inhibit the proliferation of a variety of human ovarian cancer cell lines in a dose- and time-dependent manner through activation of extracellular-signal regulated kinase (ERK) and p38 [9,10]. A second form of GnRH, GnRH-II, was expressed at the transcriptional level and GnRH-II induced an inhibition of the ovarian cancer cell growth in our previous study [11]. In addition, several in vitro investigations showed that GnRH agonists and the GnRH antagonist, i.e., cetrorelix, can inhibit the proliferation of Ishikawa and HEC1A human endometrial cancer lines and primary cultures of human endometrial cancer [12-15].Inte