前列腺素是存在人類各組織中的一種內泌素，是平衡生理環境的一個重要物質，對人體健康、疾病預防有著不可忽視的作用。它可藉由環氧合酵素(cyclooxygenase, COX)所參與的路徑在體內被合成出來。目前人體內主要有兩種cyclooxygenase被發現，分別是cyclooxygenase-1 (COX-1)及cyclooxygenase-2 (COX-2)。COX-1是一種持續性表現酵素，一般穩定的存在體內，而COX-2則是一種可誘導酵素，在受到過敏反應或細胞分裂刺激時其基因會被大量表現。
　　釩是人類在日常生活中所遭受的空氣污染源之一，其對人體的生長發育及中樞神經系統會造成嚴重傷害。根據前人研究，釩會誘導MAP kinase的訊息傳遞路徑及COX-2的表現，並導致細胞生理之改變。然而，釩對COX-2影響的機制尚不清楚。因此，本篇研究將探討釩所誘導人類肺腫瘤細胞株A549 COX-2表現的訊息傳遞路徑。
　　研究結果顯示，釩在A549細胞中會活化ERK，JNK及p38 MAPK並誘導COX-2的表現。當分別以3個MAPK的抑制劑對細胞進行前處理時，我們發現只有p38抑制劑(SB203580)會抑制釩所誘導的COX-2表現，顯示釩所誘導的MAPK中只有p38參與COX-2表現。此外，利用可偵測磷酸化的MKK3/6及ATF-2抗體，我們發現釩可誘導p38上游MKK3/6及下游ATF-2轉錄因子的磷酸化，顯示p38 MAPK訊息傳遞途徑確實參與COX-2表現。進一步以上皮生長因子受器(EGFR)之抑制劑進行前處理，結果顯示釩所誘導的COX-2表現會受到抑制。根據以上的實驗結果，我們推論釩會透過上皮生長因子受器進而活化MKK3/6，p38及ATF-2，最後導致COX-2的表現。

　Prostaglandins (PGs) were first discovered and isolated from human semen in the 1930s and were believed to be part of the prostatic secretions. PGs are produced by cyclooxygenases (COX-1 and COX-2). COX-1 is a constitutively expressed housekeeping gene whilst COX-2 is an acute phase gene that is rapidly induced by inflammatory and mitogenic stimuli.
　Vanadate is a transition metal widely distributed in the environment. It has been reported that vanadate associated with airborne particulate matters can modify DNA synthesis, cause cell growth arrest and induce apoptosis. Moreover, vanadium exposure was also found to cause increase synthesis of inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor- alpha (TNF-α), and prostaglandin E2 (PGE2). In this study, we found that exposure of A549 human lung carcinoma cells to vanadate led to extracellular signal-regulated kinase (ERK1/2), c-Jun NH2-terminal protein kinases (JNKs), p38 mitogen-activated protein kinase (p38) activation and COX-2 protein expression in a dose-dependent manner. SB203580, a p38 MAPK inhibitor, but not PD098059 and SP600125, specific inhibitor of MKK1 and selective inhibitor of JNK respectively, suppressed COX-2 expression. In addition, western blotting revealed that exposure of A549 cells to vanadate resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. Furthermore, the epithelial growth factor (EGF) receptor specific inhibitor (PD153035) abrogated vanadate-induced COX-2 expression. However, COX-2 expression was not affected by a scavenger of vanadate-induced reactive oxygen species, catalase, or DPI, an NADPH oxidase inhibitor. Together, we suggest that EGF receptor, MKK3/6, p38 MAPK and ATF-2 signaling pathways may be involved in vanadate induced COX-2 protein expression in the A549 human lung carcinoma cell.

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