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

环氧合酶-2和脂氧合酶对前列腺癌进展的影响

• 批准号: 15591676
• 负责人: MIZOKAMI Atsushi
• 金额: $ 2.24万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591676/
• 关键词: COX-2; prostate cancer; lipoxygenase; 前立腺; サイクロオキシナーゼ2; リポキシゲナーゼ; 前立腺癌; 抗癌剤抵抗性

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.

我们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，并加入COX-2代谢产物PGE2，检测VEGF启动子活性。PGE2无法识别其明显的诱导活性。接下来，我们在LNCaP-neo和COX-2过表达细胞系LNCaP-COX-2中转染将荧光素酶基因连接在PSA启动子中的载体，加入10-8 M DHT，测定PSA启动子活性。COX-2过表达的细胞系对DHT的反应性下降。这表明，当COX-2在前列腺癌中过度表达时，前列腺癌细胞通过降低雄激素反应性而变得雄激素非依赖性。用与脂肪酸代谢有关的花生四烯酸处理前列腺癌细胞，可促进细胞增殖。为了研究花生四烯酸的哪些代谢物参与其中，我们研究了COX-2抑制剂和LOX抑制剂对增殖的影响。这些抑制剂抑制了花生四烯酸的增殖，表明花生四烯酸只是作为必需的营养物质。我们还研究了COX-2过表达细胞对抗癌药物的敏感性。COX-2过表达细胞对顺铂的敏感性降低。COX-2诱导MRP2参与了这一机制。