Imai A, Takagi A, Horibe S, Takagi H, Tamaya T
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Tsukasamachi, Gifu 500-8705, Japan.
Int J Oncol. 1998 Jul;13(1):97-100. doi: 10.3892/ijo.13.1.97.
Gonadotropin-releasing hormone (GnRH) receptor-bearing tumors undergo apoptosis in vivo and in vitro with GnRH analogs. We recently showed that GnRH stimulation induces intratumoral expression of the apoptosis-inducing Fas ligand in human reproductive tract tumors. To provide a potential association of Fas/Fas ligand system with the antiproliferative signaling process of GnRH receptor, we evaluated a correlation between the Fas ligand expression and the number of viable cells in two types of GnRH receptor-bearing endometrial carcinomas that differ in Fas content. Surgically removed uterine endometrial carcinomas had been screened for the presence of GnRH receptor and Fas before analyses. Fas ligand protein was characterized by immunoblotting of membrane proteins with the specific antibody. After a lag time of 2 days, incubation with a GnRH analog leuprolide (10 microM) induced significant growth inhibition of the Fas- and GnRH receptor-bearing cells (p<0.01). Time course analysis showed that Fas ligand production, which was already observed at day 2 (p<0.01), precedes the onset of reduction in viable cell number. The stimulatory effect of GnRH on Fas ligand expression and reduction of viable cells revealed dose-dependency. The analog at concentration of 10 microM induced up to 90% reduction in cell number. In contrast, the growth of Fas-negative cells was not affected by the analog, although Fas ligand appeared in response to the GnRH analog (p<0.01). These data demonstrate that the co-presence of Fas could be essential for GnRH to promote antiproliferative action in endometrial cancer cells carrying GnRH receptor. The hormone may act through intratumor Fas and Fas ligand system to induced growth inhibition in GnRH-sensitive tumors.
携带促性腺激素释放激素（GnRH）受体的肿瘤在体内和体外均可被GnRH类似物诱导凋亡。我们最近发现，GnRH刺激可诱导人生殖道肿瘤中凋亡诱导因子Fas配体的瘤内表达。为了探究Fas/Fas配体系统与GnRH受体抗增殖信号传导过程之间的潜在关联，我们评估了两种Fas含量不同的携带GnRH受体的子宫内膜癌中Fas配体表达与活细胞数量之间的相关性。在分析之前，对手术切除的子宫内膜癌进行了GnRH受体和Fas检测。通过用特异性抗体对膜蛋白进行免疫印迹来鉴定Fas配体蛋白。经过2天的延迟期后，用GnRH类似物亮丙瑞林（10μM）孵育可显著抑制携带Fas和GnRH受体的细胞生长（p<0.01）。时间进程分析表明，Fas配体的产生在第2天就已出现（p<0.01），早于活细胞数量减少的开始。GnRH对Fas配体表达和活细胞减少的刺激作用呈现剂量依赖性。浓度为10μM的类似物可使细胞数量减少多达90%。相比之下，Fas阴性细胞的生长不受该类似物的影响，尽管Fas配体在GnRH类似物作用下出现（p<0.01）。这些数据表明，Fas的共存对于GnRH促进携带GnRH受体的子宫内膜癌细胞的抗增殖作用可能至关重要。该激素可能通过肿瘤内的Fas和Fas配体系统在GnRH敏感肿瘤中诱导生长抑制。
