Cyclooxygenase-1 is a potential target for prevention and treatment of ovarian epithelial cancer
Cyclooxygenase-1 is a potential target for prevention and treatment of ovarian epithelial cancer
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DOI：
10.1158/0008-5472.can-04-3814
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Dey, SK
中科院分区：
文献类型：
--
作者：
Daikoku, T;Wang, DZ;Dey, SK
上皮性卵巢癌（EOC）潜在的精确遗传和分子缺陷在很大程度上仍然未知，晚期疾病患者的治疗选择有限。环氧合酶（考克斯-1和考克斯-2）催化花生四烯酸转化为花生四烯酸。尽管大量证据表明考克斯-2在多种癌症中发挥作用，但对考克斯-1的作用仍研究较少。卵巢癌中考克斯异构体的表达状态也仍然令人困惑。我们先前已经证明，人类上皮性卵巢肿瘤中考克斯-1水平升高，但考克斯-2水平不变。为了更仔细地研究COX在卵巢癌中的作用，我们使用了EOC的小鼠模型，其中遗传和致癌修饰被实验性地工程化到卵巢表面上皮细胞（OSE）中，OSE被认为是人类EOC的起源细胞。这些OSE细胞在同种异体移植到宿主小鼠中时产生肿瘤。使用多种方法，我们观察到OSE细胞和由这些细胞组成的肿瘤表达高水平的考克斯-1，但不表达考克斯-2。前列环素（PGI（2））是这些细胞中考克斯-1下游产生的主要前列腺素，SC-560是一种考克斯-1选择性抑制剂，显著抑制PG 12的产生。更重要的是，当OSE细胞同种异体移植到裸鼠体内时，SC-560减少了肿瘤的生长。相反，考克斯-2选择性抑制剂塞来昔布对肿瘤生长几乎没有影响。SC-560的生长抑制作用源于细胞增殖减少和/或细胞凋亡加速。我们的研究结果表明，考克斯-1作为一个目标，为预防和/或治疗卵巢癌。
The precise genetic and molecular defects underlying epithelial ovarian cancer (EOC) remain largely unknown, and treatment options for patients with advanced disease are limited. Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostagiandins. Whereas overwhelming evidence suggests a role for COX-2 in a variety of cancers, the contribution of COX-1 remains much less explored. The expression status of COX isoforms in ovarian cancers also remains confusing. We have previously shown that human epithelial ovarian tumors have increased levels of COX-1 but not COX-2. To more carefully examine the role of COXs in ovarian cancer, we used a mouse model of EOC in which genetic and oncogenic modifications were experimentally engineered into ovarian surface epithelial cells (OSE) thought to be the cells of origin for human EOC. These OSE cells produce tumors when allografted into host mice. Using multiple approaches, we observed that OSE cells and the tumors comprised of these cells express high levels of COX-1 but not COX-2. Prostacyclin (PGI(2)) is the major prostaglandin generated downstream of COX-1 in these cells, and SC-560, a COX-1-selective inhibitor, dramatically inhibits PG12 production. More importantly, SC-560 reduced the growth of tumors when OSE cells were allografted in nude female mice. In contrast, the COX-2-selective inhibitor celecoxib had little effect on tumor growth. The growth inhibitory effects of SC-560 result from reduced cell proliferation and/or accelerated apoptosis. Our results imply COX-1 as a target for the prevention and/or treatment of EOC.