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標題: Lycopene inhibits the proliferation of androgen-dependent human prostate LNCaP tumor cells through activation of PPARγ and LXRα signaling pathway
作者: Lu, Yi-Hsuan
關鍵字: Lycopene;茄紅素;prostate cancer;PPARγ;LXRα;前列腺癌;過氧化體增殖劑活化受體;肝異受體
出版社: 食品暨應用生物科技學系所
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Epidemiological studies suggest that elevated intake of lycopene is associated with a reduced risk of several types of cancer, such as prostate cancer and hepatoma. Several studies have demonstrated that the activation of peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor alpha (LXRα) is related to reduce incidence of prostate cancer. However, the antiproliferative effects and mechanisms of lycopene on human prostate cancer are still unclear. Here, we employed androgen-dependent human prostate cancer cells (LNCaP) to examine whether lycopene inhibit the proliferation of prostate cancer via up-regulation of the expression of PPARγ and LXRα. Lycopene significantly inhibited the proliferation of LNCaP cells in a concentration
-dependent manner (2.5-10 μM) for 24, 48 and 96 hr. Lycopene treatment significantly increased protein and mRNA expression of PPARγ, LXRα for 24 and 48 hr, SREBP1 for 48 hr and ABCA1 for 96 hr, as well as decreased cellular total cholesterol level for 96 hr in a concentration-dependent manner from 2.5 to 10 μM. To further demonstrate the exactly mechanism, we added the specific antagonists of PPARγ (GW9662) and LXRα (GGPP). We found that lycopene (10 μM) + GW9662 (20 μM) or GGPP (20 μM) significantly restored the proliferation of prostate cancer cells to the control level, suppressed lycopene -induced cholesterol efflux, as well as protein and mRNA expression of PPARγ and LXRα. In summary, the present study demonstrates that lycopene inhibits the proliferation of androgen-dependent human prostate cancer LNCaP cells, and the effect is related to the activation of PPARγand LXRα signaling pathway, which then increases the expression of LXRα target genes.

流行病學研究顯示多攝取富含茄紅素的食物能降低多種癌症的發生,包括前列腺癌及肝癌。過氧化體增殖劑活化受體(PPAR)及肝異受體(LXR)的活化會降低前列腺癌的發生。然而其確切抑制前列腺癌細胞的生長機制並不清楚。因此本研究目標即在探討茄紅素在抑制前列腺癌細胞生長中所扮演的調控角色與機制為何。本研究的假說為:茄紅素會經由活化核受體PPARγ與LXRα及其標的基因的表現而抑制男性荷爾蒙依賴型前列腺癌細胞之生長。以茄紅素不同濃度(0, 2.5, 5, 10, 20 μM)分別處理男性荷爾蒙依賴型前列腺癌細胞LNCaP。結果顯示:(1) 茄紅素能抑制LNCaP細胞增生,其效果以10 μM最好;(2) 茄紅素在培養24和48小時能顯著提升LNCaP細胞中PPARγ及LXRα的蛋白與mRNA表現;(3)48小時顯著提升SREBP1的蛋白與mRNA表現;(4)96小時則顯著提升ABCA1的蛋白與mRNA表現,而且顯著降低細胞內膽固醇含量。以上作用均具有濃度效應(2.5-10 μM)。為了更進一步證明茄紅素的確是經由活化PPARγ與LXRα的表現而抑制LNCaP細胞之生長,本研究分別以PPARγ與LXRα的拮抗劑GW9662及GGPP處理LNCaP細胞。結果顯示,茄紅素(10 μM) + GW9662 (20 μM)或GGPP (20 μM)可回復LNCaP細胞生長,並且與控制組相當,同時也降低了PPARγ及LXRα的蛋白與mRNA表現,並且顯著回復茄紅素所抑制的細胞內膽固醇含量。綜合上述結果,我們證實了茄紅素可活化PPARγ及LXRα的訊息傳遞,使其標的基因表現增加,以及減少細胞內膽固醇含量,增加膽固醇輸出,而抑制男性荷爾蒙依賴型前列腺癌細胞的生長。
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