Lovastatin為膽固醇生合成路徑－Mevalonate pathway中rate-limiting step enzyme (HMG-CoA reductase)的競爭性抑制劑，是目前臨床上常用於治療高血脂相關方面的疾病。Mevalonate 為異戊二烯代謝物 (Isoprenoids)生合成路徑上之共同前驅物。研究發現，阻斷一些訊息蛋白的異戊二烯化(Isoprenylation)會影響細胞的生理功能，如：生長、分化與凋亡。先前研究指出，Statins會使Mevalonate產量下降伴隨著Ras無法進行異戊二烯化 (Isoprenylation)作用，造成Ras無法活化而抑制細胞生長訊息傳遞而達到抑制腫瘤生長。另外lovastatin亦可透過抑制histone deacetylase (HDAC)的活性而增加histone的乙醯化與p21WAF/CIP在腫瘤細胞的累積，而達到選擇性抑制腫瘤之生長。由於實驗室先前的研究發現，Eps8 (EGF receptor pathway substrate NO.8)的表達會受到Trichostatin A (TSA；是一種HDAC抑制劑)抑制，使得v-Src-transformed cells的生長情形有所影響。同時我們也發現在v-Ha-Ras transformed cells中Eps8的表現會影響Ras的訊息傳遞。因此，我們利用不同濃度的lovastatin處理v-Ha-Ras transformed cells來觀察Eps8以及其相關蛋白的表達與細胞生長的情形。我們觀察到處理lovastatin後，隨著藥物濃度的增加，細胞生長的情形有dose-dependent抑制現象，Eps8與ERK蛋白表現量也都有下降的趨勢。另外我們也利用人類大腸癌細胞株SW620及HCT116，觀察其在處理lovastatin不同濃度之下，Eps8以及其相關蛋白的表達與細胞生長的情形。我們觀察到，隨著處理lovastatin濃度的增加，細胞生長有dose-dependent抑制現象，並且與ERK蛋白活化有關。最後我們想了解TSA是否也會透過抑制Eps8而影響v-Ha-Ras transformed cells的細胞增生。我們觀察到隨著處理TSA濃度的上升，細胞增生有被抑制的現象，Eps8蛋白表現量也隨著處理TSA濃度的上升而下降。Lovastatin是HMG-CoA reductase inhibitor，因此我們推論lovastatin藉由抑制Ras，使得下游的Eps8及磷酸化ERK表現量也受到抑制，進而達到抑制細胞增生的效果。

Lovastatin inhibits the synthesis of cholesterol through competitively inhibiting the rate-limiting step enzyme HMG-CoA reductase required for the generation of mevalonate in cholesterol biosynthesis and are prescribed as anti-hyperlipoproteinemia agents. Mevalonate is a precursor of isoprene, which provides isoprenylation of many signaling proteins including Ras family proteins involved in cell growth, survival, differentiation, and motility. Thereby, lovastatin has a potential role in anti-cancer treatment. As isoprenylation of Ras is required for its appropriate cellular membrane localization , statins inhibit cell proliferation of cancer cells could be via this pathway. However, recent studies have also indicated that lovastatin could inhibit histone deacetylases activity and cause accumulation of p21WAF/CIP in tumor cells, suggesting multiple targets involved in the anti-tumor activity of lovastatin. Our previous study indicated that histone deacetylase inhibitors, such as Trichostatin A (TSA) and butyrate, could inhibit the expression of Eps8 in v-Src-transformed cells. This raises a potential mechanism for Eps8 in lovastatin-mediated growth inhibition. To prove this, we treated v-Ras-transformed cells with various concentration of lovastatin to examine its effect on cell proliferation and Eps8 expression. Our data indicated that, lovastatin inhibits Eps8 expression and cell proliferation in these cells. Besides, we treated SW620 and HCT116 cells with various concentration of lovastatin to examine its effect on cell proliferation and Eps8 expression. We observed that cell proliferation of these cells was inhibited in a dose dependent manner, which may be due to the inactivation of ERK. Finally, we want to know whether TSA affects cell proliferation of v-Ha-Ras transformed cells through inhibition of Eps8. Our data indicated that, TSA inhibits Eps8 expression and cell proliferation in these cells. In conclusion, we demonstrates lovastatin inhibits the expression of Eps8 and ERK activity through Ras, leading to decreased cell proliferation.

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