甲基轉移酶MTx在前列腺癌細胞惡化以及對賀爾蒙療法產生抗性中所扮演的角色

The role of methyltransferase MTx in prostate cancer cells progression and resistant to anti-androgen drugs treatment

黃晨銨(Chen-An Huang)

指導教授 ： 李明學

國立臺灣大學/醫學院/生物化學暨分子生物學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201902351

摘要

前列腺癌在初期治療上是透過賀爾蒙剝奪式治療，因為其在生理上需要賀爾蒙的供應來維持生存。但是賀爾蒙剝奪式療法沒辦法讓病人痊癒，甚至前列腺癌在經過一段時間治療後反而產生更嚴重的復發叫做去勢抗藥性前列腺癌，並伴隨著差勁的預後以及高度的轉移風險。在前列腺癌的進程中，其分子機制在目前還沒有非常全面的了解。根據我們實驗室先前的研究中，發現甲基化轉移酶MTx在叫惡性的前列腺癌細胞當中有更高的表現量相較於初期的前列腺癌細胞。在本篇研究中，我更進一步的測試人類前列腺癌細胞對於賀爾蒙的敏感度以及前列腺癌細胞的惡化進程。研究結果顯示，惡性前列腺癌細胞c-81 LNCaP 細胞相較於對於賀爾蒙較敏感的初期前列腺癌細胞有更高的MTx表現量。實驗中我將MTx做下調控處理，會讓惡性前列腺癌細胞c-81 LNCaP 恢復對於雄性激素的敏感度，且恢復了對於賀爾蒙治療的反應。而且我們發現，MTx會透過非直接性的方式使AR的活性增加，導致下游的目標基因被開啟。在我們的動物實驗中，我們發現使用賀爾蒙藥物與下調控MTx的惡性前列腺癌細胞能降低轉移的風險。結果合併顯示MTx在前列腺癌細胞的進程與抗藥性中扮演著重要的角色。因此，在對抗惡性前列腺癌細胞時，MTx可能成為一個新的治療性目標物。

關鍵字

抗去勢惡性前列腺癌 ； 甲基化轉移酶 ； 抗藥性 ； 雄性激素受體 ； 抗雄性激素藥物

並列摘要

Prostate cancer (PCa) often receive androgen-deprivation therapy (ADT) due to its physiological needs of androgens to survive. However, ADT is not curable. Prostate cancer frequently relapses in a certain period after ADT and acquires castration-resistant prostate cancer (CRPC) with poor prognosis and a high potential of metastasis. The molecular mechanism of how PCa progresses to CRPC is still elusive. Based on the previous finding in our laboratory that a methyltransferase MTx was up-regulated in CRPC, in this study, I further investigated the role of MTx in the androgen sensitivity of human prostate cancer cells and prostate cancer cell progression. The results showed that castration-resistant C-81 LNCaP cells expressed a high level of MTx, compared to androgen-sensitive C-33 LNCaP cells. Silencing of MTx restored the sensitivity of castration-resistant C-81 LNCaP cells to androgens. Moreover, the treatment of MTx inhibitor could re-sensitize the effectiveness of anti-androgen drugs. In addition, MTx-induced androgen receptor (AR) activity may promote AR turning on its target gene expression through an indirect pathway. In our animal study, data have shown with significant reduction of tumor volume with knockdown of MTx in castration resistant c-81 LNCaP cells with anti-androgen drug treatment. The results together may suggest that MTx plays an critical role in the progression and drug resistance of human prostate cancer. Thus, MTx may serve as an novel therapeutic target for drug development against advanced prostate cancer.

並列關鍵字

castration-resistant prostate cancer ； methyltransferase ； drug resistance ； androgen receptor ； anti-androgen drugs

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