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標題: 抑制Akt可造成攝護腺癌細胞中雄性激素受體經由Cdk5的作用而活化
Akt Inhibition Increases Androgen Receptor Activity through Cdk5 Activation in Androgen-Dependent Prostate Cancer Cells
作者: Wei-Hsiang Kao
關鍵字: 攝護腺癌;雄性激素受體;Akt;β-Catenin;Egr1;p35;週期素依賴性激酶5;細胞生長;Prostate cancer;AR;Akt;β-Catenin;Egr1;p35;Cdk5;Cell growth
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Aberrant activation of PI3K/Akt signaling has been found in different human cancer cells and supports their proliferation. Androgen receptor (AR) is critical in the early stage of prostate cancer growth. Our previous finding indicates that Cdk5 is able to increase Ser81 phosphorylation of AR and its transactivation as well as prostate cancer cell growth. However, the relationship between these two major growth regulators in androgen-dependent prostate cancer, AR and Akt, remains unclear. In this study with the experiments performed in LNCaP cells, we found that Akt inhibition by LY294002 treatment increased Egr1 expression through down-regulating β-catenin and the downstream p35 expression to Egr1 was therefore increased. Since p35 is a regulator of Cdk5 kinase, it illustrates that Akt inhibition was to activate Cdk5 and cause Ser81 phosphorylation of AR, which suggests that AR could be activated by Akt-dependent Cdk5 activation. In conclusion, although Akt inhibition is detrimental to cell growth, Cdk5-dependent AR activation becomes an alternative pathway to maintain the growth of prostate cancer cell. This finding implies that Cdk5 might serve a critical linkage between the pathways of Akt and AR and play an important role in regulating growth of prostate cancer cells under stress.

過去在不同的癌症細胞中被發現PI3K/Akt signaling的異常活化會導致其增生能力 (Proliferation) 的增強,而在攝護腺癌 (Prostate cancer) 早期發展時的生長能力中,雄性激素受體 (Androgen receptor, AR) 的活化也是非常重要的。我們實驗室過去研究發現Cdk5 (Cyclin-dependent kinase 5) 會磷酸化AR的絲氨酸第81位點 (Ser81 site),從而導致了增加其蛋白質穩定性與細胞核蛋白質表現量,進行相關下游基因的調控以及促進其生長能力,然而在雄性激素依賴型攝護腺癌中的Akt與AR此兩大主要生長調控者之間的關係仍然不甚清楚。在本次研究中,我們發現透過Akt活性抑制劑LY294002的處理之下,會減少β-catenin的蛋白質表現量與細胞核蛋白質表現量,之後並增加了Egr1的表現,進而增加了Cdk5的調控子p35的蛋白質表現量,導致了Cdk5的活性增加之後而磷酸化了AR的Ser81位點並促進了AR的穩定性與細胞核蛋白質表現量,顯示了Akt活性抑制作用會透過活化Cdk5而活化了AR。雖然Akt活性的抑制作用會降低細胞生長的能力,但透過Cdk5造成的AR活化則成為了攝護腺癌細胞中的另一種維持生長能力的訊息傳遞訊號,這樣的發現顯示了Cdk5可能在攝護腺癌細胞在經歷環境壓力之時是一個連接Akt訊息傳遞與AR訊息傳遞之間的重要關鍵因子,在生長能力中扮演兩大訊息傳遞之間的重要連結角色。
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