Effect of cyclooxygenase-2 and lipoxygenase on progression of prostate cancer

在荧光素酶基因上游连接不同长度的VEGF启动子，转染LNCaP细胞，加入考克斯-2代谢产物PGE 2，检测VEGF启动子活性，发现PGE 2无明显诱导活性。然后，我们将荧光素酶基因连接在PSA启动子中的载体转染到LNCaP-neo和考克斯-2过表达细胞系LNCaP-考克斯-2中，并加入10-8 M DHT并测量PSA启动子活性。考克斯-2过表达的细胞株对DHT的反应性下降。提示前列腺癌中考克斯-2过表达时，前列腺癌细胞通过降低雄激素反应性而成为雄激素非依赖性细胞，与脂肪酸代谢相关的花生四烯酸处理前列腺癌细胞后，可刺激细胞增殖。为了研究花生四烯酸的代谢产物参与其中，我们检测了考克斯-2抑制剂和LOX抑制剂对增殖的影响。这些抑制剂不依赖于花生四烯酸而抑制细胞的增殖，提示花生四烯酸只是作为必需的营养。我们还研究了考克斯-2过表达细胞对抗癌药物的敏感性。考克斯-2过表达的细胞对顺铂的敏感性降低。考克斯-2对MRP 2的诱导作用可能参与了这一机制。

We ligated VEGF promoter of various length in upstream of luciferase gene, transfected these in LNCaP cells, and added PGE2 which was metabolic product by COX-2, and examined VEGF promoter activity.The clear inductive activity was not recognized by PGE2. Next we transfected the vector which joined luciferase gene together in PSA promoter in LNCaP-neo and COX-2 overexpression cell line LNCaP-COX-2, and we added 10-8 M DHT and measured PSA promoter activity. The responsiveness for DHT fell with COX-2 overexpressed cell line. It was suggested that prostate cancer cells become androgen-independent via reduced androgen-responsiveness when COX-2 was overexpressed, in prostatic cancer.When prostate cancer cells were treated with arachidonic acid that was related with fatty acid metabolism, the cell proliferation was stimulated. In order to investigate which metabolites from arachidonic acid are involved in, we examined the effects of COX-2 inhibitors and LOX inhibitors on the proliferation. These inhibitors inhibited the proliferation of irrespective of arachidonic acid, suggesting that arachidonic acid just acts as essential nutrition.We also investigated that sensitivity against anti-cancer drug in COX-2 overexpressing cells. The sensitivity against cisplatin was reduced in COX-2 overexpressing cells. MRP2 induction by COX-2 was involved in this mechanism.