Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22389
標題: p35/Cdk5在cadherins/Beta-catenin調控之攝護腺癌細胞黏附接合所扮演的角色
The roles of p35/Cdk5 in cadherins/Beta-catenin-related adhesion in prostate cancer cells
作者: 陳疇丞
Chen, Chor-Chen
關鍵字: prostate cancer;轉移;metastasis;migration;Cdk5;cadherin;遷移;細胞週期依靠激酶5;黏附蛋白
出版社: 生命科學系所
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摘要: 
根據民國九十二年衛生署衛生統計資料,國人攝護腺癌(prostate cancer)發生率與死亡率有逐年上升趨勢,而相較於其它癌症的死亡個案,攝護腺癌死亡個案佔癌症總數的比例,也逐年上升。攝護腺癌轉移為攝護腺癌主要死因。一般癌細胞轉移可分為五個步驟,包括侵入(invasion)、滲入(intravasation)、滲出(extravasation)、微量轉移(micrometastasis)、巨大轉移(macrometastasis),癌細胞在侵入的過程為上皮-間葉轉變(epithelial-mesenchymal transition),最初始的階段即是必須打破細胞間的黏附接合(adhering junction)。黏附接合為細胞與細胞間主要的連接,其中E-cadherin/β-catenin為調控上皮細胞黏附接合主要複合體,N-cadherin/β-catenin為調控神經細胞黏附接合主要複合體,此外N-cadherin/β-catenin複合體也表現在一些癌細胞中。在上皮-間葉轉變中,E-cadherin為上皮標記(epithelial marker),N-cadherin為間葉標記(mesenchymal marker)。

Cdk5為絲胺酸(serine)與蘇胺酸(threonine)激酶(kinase),屬於Cdk家族,而p35為其activator。根據前人研究發現,在神經細胞內Cdk5可藉由p35與β-catenin接合,並且導致間接β-catenin之tyrosine磷酸化,使得N-cadherin/β-catenin複合體分離。抑制Cdk5活性,在神經細胞可使得N-cadherin與β-catenin連接增加;在角質細胞可使得藉由E-cadherin與β-catenin調控堆疊增加;另外,過度表現兔子水晶體上皮細胞Cdk5可減少界面活性劑不可溶性蛋白(detergent insoluble protein) N-cadherin表現。

人類攝護腺癌細胞株PC-3為同時表現N-cadherin與E-cadherin。在本篇論文研究中,證實PC3細胞內Cdk5/p35與β-catenin有交互作用。抑制Cdk5活性可抑制PC-3損傷癒合(wound closure assay),其最主要的機制為增加不可溶性E-cadherin的表現量與減少Filopodium的生成,並且利用siRNA-Cdk5抑制Cdk5的表現可增加界面活性劑不可溶性蛋白E-cadherin與β-catenin的表現。此外,Igf-1(insulin like growth factor-1,類胰島生長激素)為一穩定p35的生長激素,在本篇論文研究中發現,Igf-1處理PC-3細胞可以減少界面活性劑不可溶性E-cadherin、N-cadherin表現,但經由Cdk5抑制劑處理,可回復界面活性劑不可溶性E-cadherin、N-cadherin表現。由此,我們可以推測在PC-3細胞株中,Cdk5活性與癌細胞黏附接合以及細包移動相關。

The incidence and mortality of prostate cancer was increased in progress in Taiwan. The metastasis of prostate cancer is the key of mortality. The five steps of metastasis include invasion, intravasation, extravasation, micrometastasis and macrometastasis. The initiation step of metastasis is called invasion in which includes EMT (epithelial-mesenchymal transition) and dissociation of cell and cell adherent junction via the regulation of cadherins/β-catenin complex. E-cadherin is expression in epithelial cells and N-cadherin is expression in neural cells. E-cadherin is also considered as epithelial marker and N-cadherin is which for mesenchymal marker.

Cdk5/p35 complex is a serine/threonine kinase. It has been reported that p35, an activator of Cdk5, associates with both N-cadherin/β-catenin complex in neuronal cells and E-cadherin/β-catenin complex in human keratinocytes. p35 overexpression could result in disassociation of N-cadherin/β-catenin complex. In the other hand, inhibition of Cdk5/p35 activity led to increase N-cadherin-mediated adhesion in neuronal cells and E-cadherin-mediated adhesion in human keratinocytes, respectively. In addition, Cdk5 overexpression could reduce expression of detergent-insoluble N-cadherin in rabbit lens epithelial cells.

Our strategy is taking advantage of cell culture system of prostate cancer cell line, PC-3, which contains both N- and E-cadherin protein expressions. The present results demonstrated that, Cdk5 inhibition by treatment of roscovitine (RV) could reduce cell migration measured by wound closure assay. The molecular mechanism was addressed on the rising expression of detergent-insoluble E-cadherin. In addition, transfected siRNA-Cdk5 in PC-3 cells could reduce expression of Cdk5 and increase expression of detergent-insoluble E-cadherin and β-catenin. On the other hand, detergent-insoluble N-cadherin, E-cadherin and β-catenin in PC-3 cells were down-regulated by treatment with insulin-like growth factor 1 (IGF-1, as a stabilizer of p35 protein). In addition, the IGF-1-dependent effects above could be reversed by treatment of RV. In conclusion, we suggest that p35/Cdk5 might play an important role in regulating cadherin/β-catenin-related adhesion and cell migration in prostate cancer cells.
URI: http://hdl.handle.net/11455/22389
其他識別: U0005-2407200622521000
Appears in Collections:生命科學系所

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