Sheng H, Shao J, Morrow J D, Beauchamp R D, DuBois R N
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279, USA.
Cancer Res. 1998 Jan 15;58(2):362-6.
Previously, we have shown that forced expression of prostaglandin endoperoxide synthase-2 [also called cyclooxygenase (COX) 2] leads to inhibition of programmed cell death in intestinal epithelial cells. More recently, we have demonstrated that growth of human colonic cancer xenografts is inhibited by treatment with a highly selective COX-2 inhibitor in tumors that express COX-2 (HCA-7) but not in those that lack COX-2 expression (HCT-116). To explore the biochemical mechanisms involved in these effects, we have evaluated the role of COX-2-derived eicosanoid products on programmed cell death in human colon cancer cells. Here we report that PGE2 treatment of human colon cancer cells leads to increased clonogenicity of HCA-7, but not HCT-116 cells. Treatment with a highly selective COX-2 inhibitor (SC-58125) decreases colony formation in monolayer culture and this growth inhibition was reversed by treatment with PGE2. Additionally, PGE2 inhibits programmed cell death caused by SC-58125 and induces Bcl-2 expression, but did not affect Bcl-x or Bax expression in human colon cancer (HCA-7) cells. Therefore, decreased cell death caused by PGE2 would enhance the tumorigenic potential of intestinal epithelial cells. Thus, these results may help to explain a component of the mechanism by which COX inhibitors prevent colorectal cancer in humans.
此前，我们已经表明，前列腺素内过氧化物合酶-2（也称为环氧化酶（COX）2）的强制表达会导致肠上皮细胞中程序性细胞死亡受到抑制。最近，我们证明，在表达COX-2的肿瘤（HCA-7）中，用高度选择性的COX-2抑制剂治疗可抑制人结肠癌异种移植瘤的生长，但在缺乏COX-2表达的肿瘤（HCT-116）中则不然。为了探究这些效应所涉及的生化机制，我们评估了COX-2衍生的类花生酸产物在人结肠癌细胞程序性细胞死亡中的作用。在此我们报告，用前列腺素E2（PGE2）处理人结肠癌细胞会导致HCA-7细胞的克隆形成能力增加，但对HCT-116细胞则无此作用。用高度选择性的COX-2抑制剂（SC-58125）处理会减少单层培养中的集落形成，而这种生长抑制作用可通过用PGE2处理来逆转。此外，PGE2可抑制由SC-58125引起的程序性细胞死亡并诱导Bcl-2表达，但不影响人结肠癌（HCA-7）细胞中的Bcl-x或Bax表达。因此，PGE2引起的细胞死亡减少会增强肠上皮细胞的致瘤潜能。因此，这些结果可能有助于解释COX抑制剂预防人类结直肠癌的部分机制。
