Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
Department of Urology, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
Diabetes. 2014 Nov;63(11):3891-905. doi: 10.2337/db13-1169. Epub 2014 May 30.
Recently, pleiotropic benefits of incretin therapy beyond glycemic control have been reported. Although cancer is one of the main causes of death in diabetic patients, few reports describe the anticancer effects of incretin. Here, we examined the effect of the incretin drug exendin (Ex)-4, a GLP-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after they had undergone radical prostatectomy, GLP-1R expression colocalized with P504S, a marker of prostate cancer. In in vitro experiments, Ex-4 significantly decreased the proliferation of the prostate cancer cell lines LNCap, PC3, and DU145, but not that of ALVA-41. This antiproliferative effect depended on GLP-1R expression. In accordance with the abundant expression of GLP-1R in LNCap cells, a GLP-1R antagonist or GLP-1R knockdown with small interfering RNA abolished the inhibitory effect of Ex-4 on cell proliferation. Although Ex-4 had no effect on either androgen receptor activation or apoptosis, it decreased extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation in LNCap cells. Importantly, Ex-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCap cells into athymic mice and significantly reduced the tumor expression of P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that Ex-4 attenuates prostate cancer growth through the inhibition of ERK-MAPK activation.
最近，有研究报道肠促胰岛素疗法除了血糖控制之外还有多种益处。尽管癌症是糖尿病患者的主要死亡原因之一，但很少有报道描述肠促胰岛素的抗癌作用。在这里，我们研究了肠促胰岛素药物 exendin（Ex）-4（一种 GLP-1 受体（GLP-1R）激动剂）对前列腺癌的影响。在接受根治性前列腺切除术的患者的前列腺癌组织中，GLP-1R 表达与 P504S 共定位，P504S 是前列腺癌的标志物。在体外实验中，Ex-4 显著降低了前列腺癌细胞系 LNCap、PC3 和 DU145 的增殖，但对 ALVA-41 没有作用。这种增殖抑制作用依赖于 GLP-1R 的表达。与 LNCap 细胞中 GLP-1R 的丰富表达一致，GLP-1R 拮抗剂或 GLP-1R 小干扰 RNA 敲低消除了 Ex-4 对细胞增殖的抑制作用。虽然 Ex-4 对雄激素受体激活或细胞凋亡没有影响，但它降低了 LNCap 细胞中细胞外信号调节激酶（ERK）-丝裂原活化蛋白激酶（MAPK）磷酸化。重要的是，Ex-4 减弱了 LNCap 细胞移植到无胸腺小鼠中诱导的体内前列腺癌生长，并显著降低了肿瘤中 P504S、Ki67 和磷酸化 ERK-MAPK 的表达。这些数据表明，Ex-4 通过抑制 ERK-MAPK 激活来减轻前列腺癌的生长。
