Kim Ki-Yon, Choi Kyung-Chul, Auersperg Nelly, Leung Peter C K
Department of Obstetrics and Gynecology, British Columbia Children's and Women's Hospital, Child and Family Research Institute, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5.
Endocr Relat Cancer. 2006 Mar;13(1):211-20. doi: 10.1677/erc.1.01033.
In our previous studies, we demonstrated that ERK1/2 (extracellular signal-regulated protein kinase) and p38 MAPK (mitogen-activated protein kinase) are required for gonadotropin-releasing hormone (GnRH)-II-induced anti-proliferation of ovarian cancer cells. In the present study, we examined the role of the GnRH-I receptor, as well as the activation of protein kinase C (PKC), in the anti-proliferative effect induced by GnRH-I or II in ovarian cancer cells. Our results demonstrated that Antide, a GnRH-I antagonist, reversed the activation of ERK1/2 induced by GnRH-I or II and abolished the anti-proliferative effect of GnRH-I and II in ovarian cancer cells. Transfection of short-interfering RNA to abrogate the gene expression of the GnRH-I receptor reversed GnRH-I and II-induced anti-proliferation. These results indicate that GnRH-I or II induce anti-proliferation through the GnRH-I receptor in ovarian cancer cells. In addition, the activation of ERK1/2 by GnRH-I or II was mimicked by phorbol-12-myristate 13-acetate, a PKC activator. Pretreatment with GF109203X, an inhibitor of PKC, blocked GnRH-induced ERK1/2 activation and anti-proliferation. These results suggest that the activation of PKC is responsible for GnRH-induced ERK1/2 activation and anti-proliferation in ovarian cancer cells. Taken together, these results indicate that binding of GnRH-I and II to the GnRH-I receptor activates ERK1/2 through a PKC-dependent pathway and is essential for GnRH-induced anti-proliferation of ovarian cancer cells.
在我们之前的研究中，我们证明了细胞外信号调节蛋白激酶（ERK1/2）和丝裂原活化蛋白激酶（p38 MAPK）是促性腺激素释放激素（GnRH）-II诱导卵巢癌细胞抗增殖所必需的。在本研究中，我们研究了GnRH-I受体的作用以及蛋白激酶C（PKC）的激活在GnRH-I或II诱导的卵巢癌细胞抗增殖效应中的作用。我们的结果表明，GnRH-I拮抗剂Antide可逆转GnRH-I或II诱导的ERK1/2激活，并消除GnRH-I和II在卵巢癌细胞中的抗增殖作用。转染短干扰RNA以消除GnRH-I受体的基因表达可逆转GnRH-I和II诱导的抗增殖作用。这些结果表明，GnRH-I或II通过卵巢癌细胞中的GnRH-I受体诱导抗增殖。此外，PKC激活剂佛波醇-12-肉豆蔻酸酯13-乙酸酯可模拟GnRH-I或II对ERK1/2的激活。用PKC抑制剂GF109203X预处理可阻断GnRH诱导的ERK1/2激活和抗增殖作用。这些结果表明，PKC的激活负责GnRH诱导的卵巢癌细胞中ERK1/2的激活和抗增殖。综上所述，这些结果表明，GnRH-I和II与GnRH-I受体的结合通过PKC依赖性途径激活ERK1/2，并且对于GnRH诱导的卵巢癌细胞抗增殖至关重要。
