前列腺素D2 (PGD2) 在許多病理與生理反應的過程扮演一個調節的角色，包括血管新生、發炎反應及腫瘤生成。前列腺素D2有兩個主要的特性，包括自發性地代謝為其他具活性的前列腺素分子，以及在許多反應中能與其專一受器DP和 CRTH2/DP2結合，以活化下游訊息傳遞路徑。前列腺素D2主要是在發炎反應中，經由肥大細胞釋放出來，並進一步調節包括呼吸道、肺部、骨質及免疫系統等部位的發炎反應。尤其是在肺組織當中，常見的氣喘、咳嗽等反應都會造成肥大細胞致敏化，並釋放出大量的前列腺素D2。前人研究評比臨床病人中肺癌組織及正常肺組織產生前列腺素的量，發現相較於正常肺組織，肺癌組織中前列腺素E2的生成量明顯提高；反之，前列腺素D2的生成量卻明顯降低。近十年的研究，證實了前列腺素E2確實能經由其專一受器促進腫瘤的生成。然而，在支氣管上皮及肺組織等前列腺素D2會大量生成的部位，儘管許多文獻針對氣喘或發炎反應進行研究，但這些組織中針對前列腺素D2調控細胞凋亡或抑制細胞增生的機制卻尚未釐清。
為了研究在肺組織中，前列腺素D2影響腫瘤生成的機制，實驗選用非小細胞肺癌細胞株A549 ，並以前列腺素D2及其代謝物，15d-前列腺素J2進行各種條件的處理。本研究主要分為兩個部份，包括前列腺素D2如何引起細胞凋亡和細胞凋亡的機制。論文內容首先證實前列腺素D2的確會經由粒線體相關路徑引起細胞凋亡反應。另外，透過阻斷前列腺素D2專一受器活化、抑制p38 MAPK、ERK的活性和改變前列腺素D2代謝的路徑，實驗結果顯示前列腺素D2並非經由活化其專一受器或MAPKs訊息傳遞路徑引起細胞凋亡。在非小細胞肺癌細胞株A549中，前列腺素D2主要是自發性代謝為15d-前列腺素J2，並藉其代謝的前列腺素引起細胞凋亡反應。而前列腺素D2專一受器和MAPKs的活化則可能與前列腺素D2刺激發炎反應有關。確認前列腺素D2的代謝物是前列腺素D2誘導肺癌細胞株細胞凋亡的關鍵後，實驗進一步探討前列腺素D2的代謝物，15d-前列腺素J2是透過何種機制造成非小細胞肺癌細胞株A549的細胞凋亡。先前研究指出，在許多不同組織中，15d-前列腺素J2會經由活化PPARγ和引發ROS生成以誘導細胞凋亡反應。透過阻斷PPARγ的活化和降低ROS生成的實驗, 結果顯示15d-前列腺素J2主要是引發ROS產生進而引起一連串caspase的活化，導致細胞凋亡的發生。本篇論文的結果指出前列腺素D2誘導非小細胞肺癌細胞株A549細胞凋亡的機制，主要是前列腺素D2自發性代謝為15d-前列腺素J2，再透過15d-前列腺素J2引發ROS產生，依循這條非PPARγ活化路徑引起連續性地caspase的活化，造成細胞凋亡。

Prostaglandin D2 (PGD2) is a mediator in various pathophysiological processes, including angiogenesis, inflammation and tumorigenesis. PGD2 can be converted to active metabolites and is known to activate two selective receptors, DP and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2/DP2). PGD2 is the principal PG released by mast cells during inflammation, and it regulates inflammation in tissues of the airway, lung, bone and immune system. Large amounts of PGD2 are released by sensitized mast cells during inflammation in the lung tissue. In the past, McLemore et al. reported that the production of PGs in lung cancer (LC) and normal lung (NL) tissue from individual patients demonstrated increased biosynthesis of prostaglandin E2 (PGE2) and lower levels of PGD2 in LC compared to NL tissue. In recent studies, PGE2 has been demonstrated to play an important role in tumorigenesis. Despite the clear inflammatory effects of PGD2 and its production in large amounts in bronchial epithelia and lung cells, the apoptotic regulation by PGD2 in these tissues is still unknown.
To investigate the regulated mechanism of PGD2 in lung tumorigenesis, A549 cells, one type of non-small cell lung carcinomas (NSCLCs), were chosen and exposed to PGD2 or its metabolite, 15d-PGJ2, under various conditions. In this thesis, we determined that PGD2 can induce cellular apoptosis via mitochondrial pathway by immunocytochemistry and Western blot analysis in A549 cells. In addition, we determined the mechanism of PGD2-induced apoptosis in A549 cells. In the other experiments, we blocked several PGD2-induced signaling pathways by antagonists and inhibitors, including BWA868C, ramatroban, SB203580, PD98059 and human serum albumin (HSA). We discovered that apoptosis in A549 cells by PGD2 was induced by its metabolite, 15d-PGJ2, which was converted from PGD2 spontaneously, and the induction was neither via PGD2 selective receptors nor through the MAPK signaling pathways. Activation of DP, CRTH2/DP2 and several MAPKs by PGD2 might be involved in the PGD2-induced inflammation. Because this metabolite of PDG2 is the key in the PGD2-induced apoptosis, then the thesis is to further study how the PGD2 metabolite, 15d-PGJ2, induces apoptosis in A549 cells. Previous studies had reported that 15d-PGJ2 can induce apoptosis via peroxisome proliferator-activated receptor gamma (PPARγ) activation and reactive oxygen species (ROS) formation in many cell types. We determined the mechanism of 15d-PGJ2-induced apoptosis in A549 cells by blocking the activation of PPARγ and ROS formation, using GW9662, PPARγ knockdown, quercetin and N-Acetyl-L-Cysteine (NAC). By blocking the activation, we found that 15d-PGJ2 induced activation of caspase cascade and reduced cellular defense to decrease survival capability, including GSH, SOD activity, phosphorylation of Akt, and total Akt in A549 cells. All these results indicate that the mechanism of PGD2-induced apoptosis in A549 cells was via its metabolite, 15d-PGJ2, and activation of caspase cascade was through ROS mediated and PPARγ-independent pathway.

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