- 學位論文
探討希樂葆在攝護腺癌細胞移動、侵襲以及間質蛋白酶活化的影響
Suppression of prostate cancer cell migration and invasion by celebrex through down-regulating matriptase activity
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摘要
攝護腺癌的致死率在西方男性世界中排名第二位；在台灣，攝護腺癌的發生率以及死亡率亦有逐年增加的趨勢。有些研究指出發炎與攝護腺癌的產生以及惡化有關。希樂葆 (Celebrex) 是一種亞型環氧化酶 (Cyclooxygenase-2, COX-2) 抑制物，近年研究指出希樂葆具有抗發炎、抗癌以及預防癌症產生 (chemoprevention) 的功能。然而，希樂葆是如何抑制攝護腺癌細胞侵襲的分子機制尚未清楚了解。在本篇研究裡，我們建立了攝護腺癌細胞侵襲能力進化的細胞模式 (PC-3以及M2I2 PC-3細胞)，並發現幾個發炎相關蛋白，亞型環氧化酶、磷酸化JUN激酶以及第一型介白素在M2I2 PC-3細胞的表現量增加。進而檢測了希樂葆對於攝護腺癌PC-3細胞的生長、移動與侵襲的影響。實驗結果指出希樂葆可有效地抑制攝護腺癌細胞的生長、移動與侵襲能力。為了更進一步研究希樂葆抑制攝護腺癌細胞移動與侵襲的分子機制，我探討希樂葆對於間質蛋白酶 (Matriptase) 可能的影響。間質蛋白酶是第二型嵌膜絲胺酸蛋白酶，近年來研究指出異常活化的間質蛋白酶與許多癌症的演進有相關聯，包括攝護腺癌。本篇實驗結果指出，希樂葆可以降低間質蛋白酶的表現以及釋出到細胞外的量；此量的降低，主要藉由抑制間質蛋白酶基因的表達以降低其表現量。更進一步地，在兩株不具亞型環氧化酶的攝護腺癌DU-145和LNCaP細胞中，希樂葆一樣可以藉由降低間質蛋白酶活化及表現量來抑制這兩種癌細胞的移動與侵襲能力。同時發現，在所有市面上可購得的非類固醇抗炎藥物中，希樂葆是最具潛力的藥物可抑制攝護腺癌細胞的間質蛋白酶活化。同時亞型環氧化酶主要產物PGE2可刺激間質蛋白酶的活化。為了更進一步了解PGE2如何促進間質蛋白酶的活化，我使用不同的EP接受器抑制物並發現EP1接受器可能參與間質蛋白酶的活化。整體來說，本論文實驗結果指出希樂葆具有抑制間質蛋白酶功能以及壓抑攝護腺癌細胞侵襲的能力。因此希樂葆是一個未來具有潛力的藥物，可用以抗攝護腺癌或預防此癌症的產生。
並列摘要
Prostate cancer is the second leading cause of cancer-related death in men of the western world. In Taiwan, the incidence and mortality of prostate cancer (PCa) have been rising progressively in recent years. Several studies have showed that inflammation is involved in the development and progression of PCa. Celebrex, a COX-2 specific inhib¬itor, has been shown with anti-inflammatory, anti-carcinogenic, and chemopreventive effects. However, the molecular mechanism how celebrex suppresses PCa cell invasion is not well understood. In this study, we established a PC-3 cell invasion progression model (parental and M2I2 PC-3 cells) and found that several inflammation-associated proteins, COX-2, p-JNK and IL-1β were up-regulated in M2I2 PC-3 cells. The results showed that celebrex could significantly suppress PCa cell migration and invasion, at least in part, due to down regulation of a tumor-promoting serine protease matriptase at the gene expression and activation levels. Similarly, celebrex also can execute its anti-cancer properties in two COX-2-null PCa DU-145 and LNCaP cells, via a similar mechanism as shown in PC3 cells. Furthermore, PGE2, a main product of COX-2, could induce matriptase activation and its EP1 receptor was identified to be involved in matriptase activation in PCa cells. Taken together, the data indicated that celebrex exhibits a suppressive effect on PCa cell migration and invasion, at least in part, by down-regulating matriptase function.
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