Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23806
標題: Finasteride藉由干擾雄性激素受體蛋白質穩定性抑制A549細胞生長
Finasteride Suppresses Proliferation of A549 Cells through Interfering Androgen Receptor Protein Stability
作者: 連傳岳
Lien, Chuan-Yuen
關鍵字: lung cancer;肺癌;androgen receptor;finasteride;雄性激素受體;柔沛
出版社: 生命科學系所
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摘要: 
流行病學臨床調查研究顯示,性別差異與肺部疾病的發生率呈正相關性,男性比女性更容易得到腫瘤與非腫瘤性的肺部疾病,且肺癌患者中女性生存率明顯高於男性。相較於正常肺部組織,雄性激素受體 (androgen receptor, AR) 在惡性腫瘤中也有較高的表現情況,此證據顯示AR的調節可能涉及了肺癌的發病機制。Finasteride是5α-還原酶 (5α-reductase) 的特異性抑制劑,其有效抑制睪固酮 (dihydrotestosterone, DHT) 的產生,廣泛的應用在不同雄性荷爾蒙過度表現的病灶,在臨床上作為良性前列腺增生症 (benign prostatic hyperplasia, BPH) 患者的第一線口服治療用藥。先前研究結果顯示,前列腺癌細胞株對於finasteride的治療也很敏感,可有效的治療雄性激素依賴性前列腺癌細胞的增生。因此,本論文的研究目的在於探討AR在非小細胞肺癌 (non-small cell lung cancer, NSCLC) 中所扮演的角色以及finasteride調控AR蛋白質表現的相關機制。研究結果發現,透過轉染方式過度表現AR可以刺激非小型細胞肺癌細胞株A549的增生,反之使用shRNA與AR抑制劑可以降低A549的生長,顯示AR在NSCLC的生長中扮演著重要的角色,暗示著在腫瘤和非腫瘤性肺部疾病中,AR具有治療肺病患者潛在應用價值。在此論文中,我們探討finasteride是否透過干擾AR的蛋白穩定性來調控NSCLC的生長。實驗結果顯示finasteride處理會抑制A549生長,且抑制生長效果與finasteride使用劑量與處理時間呈正相關。在A549中發現finasteride會導致AR蛋白量下降,此外亦發現finasteride同時也會減少AR進入細胞核,降低AR的轉錄活性,並對於finateride導致的AR蛋白量下降,排除了finasteride對基因表現影響。進一步我們發現finasteride抑制了AR與熱休克蛋白90 (heat-shock protein 90, HSP 90) 的結合而降低了AR蛋白質穩定性,導致Mdm2與AR鍵結提高而增加ubiquitination,促使AR走向proteasome-dependent的降解路徑。除此之外finasteride透過累積細胞週期導致細胞週期G1阻滯,並發現促凋亡蛋白(Bax)表現增加和抗凋亡蛋白(Bcl-2)表現減少,TUNEL assay結果顯示DNA 斷裂 (DNA fragment) 數量的提高,皆顯示finasteride誘導A549發生細胞凋亡。綜合上述數據,finasteride誘導細胞週期停滯在G1期與增加細胞凋亡,抑制A549的AR蛋白質穩定性與細胞增生。經由以上研究結果,發現 finasteride可能是一個潛在的治療非小細胞肺癌的治療劑,期望這個研究,可以對於未來肺癌的診斷及治療有所貢獻。

The previous epidemiological studies have reported that gender differences exist in clinical corroboration in human lung diseases. In particular, men are more probability developed than women both neoplastic and non-neoplastic lung diseases. Female patients with lung cancer survival rate were significantly higher than male patients. Androgen receptors (AR) in malignant tumors have a higher performance compared to normal lung tissue. This gender difference above suggests that regulation of AR may be involved in the pathogenesis of human lung cancer. Finasteride is a specific inhibitor of the 5α-reductase and used as a first-lined medicine for benign prostatic hyperplasia (BPH) patients due to decreasing the conversion of testosterone into dihydroteststosterone, a potent form of androgen. To focus that extensive application excessively expressed in the different male hormone. Previous results indicate that the proliferation of prostate cancer cells is decreased with finasteride treatment. Interestingly, androgen-dependent prostate cancer cell lines are also sensitive to finasteride treatment. In this study, we verify the role of AR in non-small cell lung cancer and the mechanism of finasteride in AR regulation. The cell growth tests results show that AR overexpression by transient transfection increased the cell proliferation of A549 cells. On the other hand, knockdown AR expression by shRNA and AR inhibitor, casodex, could inhibit cell growth of A549 cells. Display AR plays an important role in the growth of NSCLC. It appears the potential roles of AR in both neoplastic and non-neoplastic lung diseases toward improved treatment options for the patients. In this study, we investigated whether finasteride could affect cell viability of NSCLC. Finasteride potently inhibited growth of NSCLC cell line, A549, in a dose- and time-dependent manner. However, finasteride decreased AR protein expression excludes mRNA level in A549, and resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Furthermore, we found that finasteride decreased the complex of AR and heat-shock protein 90 (HSP 90), and reduce the protein stability of AR. Simultaneously, finasteride increased the association of AR and Mdm2, which in turn induced AR degradation through proteasome-mediated pathway, resulting in AR protein expression decreased. Moreover, there was an increase in the number of cells accumulating in the G1 phase of the cell cycle, resulted in cell cycle G1 arrest. In addition, finasteride induced apoptosis of NSCLC which is mediated through up-regulating pro-apoptotic protein expression (Bax) and down-regulating anti-apoptotic protein expression (Bcl-2). It consists with the determination of finasteride-induced DNA fragmentation in A549 through the TUNEL assay. Based on above data, finasteride suppressed AR protein stability and cell proliferation via inducing cell cycle arrest at G1 phase and apoptosis. Taken together, these results suggest that finasteride might be a potential therapeutic agent for treating the NSCLC. We hope these findings in the future can contribute to diagnosis and treatment of lung cancer.
URI: http://hdl.handle.net/11455/23806
其他識別: U0005-2606201214072400
Appears in Collections:生命科學系所

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