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標題: Her2經由影響Cdk5激酶活性及AR轉錄活化以調控人類攝護腺癌細胞生長
Her2 modulates Cdk5-dependent AR activation and cell proliferation in human prostate cancer
作者: 許馥甯
Hsu, Fu-Ning
關鍵字: androgen receptor;雄性激素受體;prostate cancer;攝護腺癌
出版社: 生命科學系所
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Cyclin-dependent kinase 5 (Cdk5) 蛋白於Cdk家族中屬於獨特的ㄧ員,其並不涉及細胞週期的調控,且激酶活性不需由cyclin蛋白所啟動。近十多年來,Cdk5及其專一活化蛋白p35之功能被熱烈探討於中樞神經系統與神經退化性疾病中。然而,在人類惡性腫瘤方面,Cdk5則是近年來被研究的新興蛋白質。本論文的實驗結果顯示,Cdk5及p35蛋白皆表現於有雄性激素受體(androgen receptor, AR)的LNCaP細胞(人類攝護腺癌細胞株)中。AR是配體依賴核轉錄因子,調控著攝護腺癌細胞之增生。首先利用免疫沉澱法及免疫細胞化學染色法確認Cdk5、p35及AR蛋白間的生化交互作用。在有R1881(人工合成的雄性激素)處理下,過度表現Cdk5或p35蛋白會提高AR蛋白Ser81位置之磷酸化及AR本身蛋白表現。反之,Ser81位置的磷酸化、AR蛋白穩定度及AR蛋白於細胞核內之分佈,則會受到Cdk5活性抑制劑roscovitine (Rv)的處理而被抑制。此外,抑制掉Cdk5活性也會抑制AR下游調控基因,攝護腺特異抗原(PSA)的表現及外泌。而MTT分析的結果也顯示,Cdk5活性調控了LNCaP細胞之增生。在攝護腺癌最新的研究顯示,Her2-ErbB3受體能經由透過下游訊息路徑以增加AR蛋白Ser81的磷酸化,而此路徑已證實並非PI3K/Akt路徑。我們首先利用免疫沉澱法確認Her2-ErbB3受體與Cdk5-p35蛋白間的交互關係。前人的研究顯示,Cdk5蛋白Tyr15位置的磷酸化可用以代表其活性的上升。而在Her2活性抑制劑AG825的處理下,Cdk5蛋白Tyr15的磷酸化及下游AR蛋白穩定度也會受到抑制。反之,生長因子heregulin (HRG)的加入,則可使Her2-ErbB3受體透過Cdk5增加AR蛋白Ser81磷酸化以及攝護腺癌細胞的增生。除了AR蛋白以外,STAT3蛋白也是被廣泛研究的轉錄因子。Cdk5蛋白可與STAT3進行交互作用,並磷酸化STAT3蛋白的Ser727位置。在本實驗室甲狀腺癌的研究發現,Her2受體會透過磷酸化Cdk5激酶Tyr15的位置,進而磷酸化STAT3蛋白。而本論文題目的研究顯示,Her2受體的活性調控了Cdk5與STAT3之間的交互作用,以及STAT3蛋白Ser727位置的磷酸化。綜合以上結果,Her2-Cdk5路徑對於AR和STAT3蛋白功能及攝護腺癌細胞增生的調控扮演了重要的角色,並且為治療攝護腺癌的基礎醫學研究提供了ㄧ個新方向。同時也可能為ErbB受體蛋白在腫瘤生物學上繼乳癌後開啟新的一頁。

Cyclin-dependent kinase 5 (Cdk5) is a unique member of Cdk family without involving cell cycle regulation. The functions of Cdk5 and its neuron-specific activator p35 were extensively explored in both neuronal development and neurodegenerative disease in recent decades. However, the roles of Cdk5 are still unclear in human cancers and need to be further investigated. Our results demonstrated that expression of Cdk5 and p35 protein was present in LNCaP cells (human prostate cancer cell line) which harbored expression of androgen receptor (AR). AR is a ligand-dependent nuclear transcription factor that mediates prostate cancer cell proliferation. The triple complex of Cdk5, AR, and p35 was first identified by immunoprecipitation and immunocytochemistry. Under the treatment of R1881 (synthetic androgen), we found that the levels of phosphorylation of AR Ser81 site and AR protein were increased by overexpression of Cdk5 or p35. In addition, phosphorylation (S81), protein stability and nuclear translocation of AR were all affected by the specific Cdk5 activity inhibitor (roscovitine). Moreover, Cdk5 inhibition decreased both expression and secretion of AR downstream gene, prostate-specific antigen (PSA). The up-to-date research of prostate cancer indicated that Her2-ErbB3 provided signals to regulate AR activation except through PI3k/Akt pathway. The biochemical interactions among Her2-ErbB3 and Cdk5-p35 were first identified by immunoprecipitation. The Tyr15 phosphorylation of Cdk5 was indicated to represent its rising activity. The Tyr15 phosphorylation of Cdk5 and AR protein stability were declined by the specific Her2 activity inhibitor (AG825). In addition to AR, STAT3 was another transcription factor enthusiastically discussed in human cancer cells. Cdk5 was reported to be a kinase corresponding to Ser727 phosphorylation of STAT3. The interaction among STAT3, Cdk5 and p35 was also recognized by immunoprecipitation. The level of STAT3 Ser727 phosphorylation was paralleled to Cdk5 protein expression. Besides, the Her2 activity-dependent interaction between STAT3 and Cdk5 was determined by immunoprecipitation. Furthermore, the HRG-induced LNCaP cell growth was significantly blocked by roscovitine, which indicating that HRG modulated cell growth through Cdk5 activity. Taken together with these results, Her2-ErbB3 might play important roles in regulating AR/STAT3 functions and prostate cancer cell proliferation through Cdk5 activity, and Her2-Cdk5-AR/STAT3 axis might be potential therapeutic targets to prostate cancer.
其他識別: U0005-0708200720594200
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