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The Effects of Retinoic Acid on Cdk5 and p35-Related Proliferation, Differentiation, and Apoptosis of Prostate Cancer Cells
|作者:||林赫||關鍵字:||基礎研究;Cdk5;基礎醫學類, 生物科學類, 藥學;Cdk5蛋白;p35蛋白;維生素甲酸;ErbB 蛋白;p35;retinoic acid;ErbB||摘要:||
Cdk5蛋白在中樞神經系統發育及神經退化性疾病(如阿茲海默症)中扮演的角色於近年來被踴躍地討論。本實驗室自成立以來致力於探討Cdk5蛋白在人類腫瘤細胞中的重要性，已發表之研究成果顯示Cdk5蛋白對於髓質性甲狀腺癌細胞生長及癌化扮演重要角色；Cdk5蛋白於攝護腺癌細胞中可受到藥物過度活化而導致癌細胞凋亡。95年度國科會計畫初步結果指出Cdk5蛋白於攝護腺癌細胞中會調控雄性激素受體(androgen receptor, AR)而刺激癌細胞生長。此外，本實驗室亦證實近年來被認為在攝護腺癌中日益重要的ErbB家族蛋白與Cdk5間的交互關係。另一方面，維生素甲酸為一具有悠久歷史用於致腫瘤分化的藥物，且被認為可使神經細胞中Cdk5蛋白活性上升而導致神經細胞進行分化。基於以上背景，本計畫的目的在於探討維生素甲酸是否藉由直接影響Cdk5與p35蛋白表現與活性而影響攝護腺癌細胞之生長、分化與凋亡，或是經由誘導細胞內鈣離子上升而活化ErbB家族蛋白後，間接刺激Cdk5蛋白活性。首先將探討維生素甲酸是否影響Cdk5與p35蛋白表現及活性，對於攝護腺癌細胞生長、分化與凋亡的影響；第二，檢測cAMP相關訊息途徑於攝護腺癌細胞中是否參與維生素甲酸對於Cdk5與p35蛋白及活性的影響；第三，探討維生素甲酸是否影響Cdk5與p35相關之下游雄性激素受體的訊息傳遞；第四，觀察攝護腺癌細胞中Cdk5與p35蛋白表現及活性受到維生素甲酸作用後細胞週期及相關蛋白調控的影響；第五，觀察維生素甲酸對於攝護腺癌細胞於裸鼠皮下生長、分化及凋亡的改變是否受到Cdk5與p35蛋白及活性的影響 (請見計畫內容之實驗設計圖)。綜合我們的初步及預期結果(詳見結果預測圖及附件初步結果)，維生素甲酸可能透過直接調控Cdk5與p35蛋白及活性或間接活化ErbB家族蛋白而調控Cdk5與p35蛋白及活性達成影響攝護腺癌細胞分化與凋亡的目的。相信以上的研究成果對於攝護腺癌細胞的特性及癌症治療將有更進一步的發展。
Cdk5 is enthusiastically discussed about its roles in central nervous development and neurodegeneration (such as Alzheimer's disease). Recently, our lab made efforts in exploring the roles of Cdk5 in human tumor cells. The published results demonstrated that Cdk5 plays an important role in tumorigenesis of medullary thyroid carcinoma cells. In addition, drug-induced Cdk5 overactivation was also found to cause apoptosis of prostate cancer cells. The preliminary results of 2006-NSC grant indicated that Cdk5 could regulate androgen receptor (AR) transactivation and downstream proliferation of prostate cancer cells. Furthermore, we also identified the protein interaction between ErbB family protein and Cdk5. In addition, an old-history drug for tumor differentiation, retinoic acid (RA), was believed to activate Cdk5 kinase activity and cause neuronal differentiation. According to the decriptions above, the goal of this grant is to understand whether the roles of RA on growth, differentiation, and apoptosis of prostate cancer cells are directly through regulating the expression and kinase activity of Cdk5 and its activator, p35, or whether the roles of RA on regulating Cdk5 activity are indirectly through intracellular calcium-dependent ErbB activation. First, the effects of RA on Cdk5-p35-dependent growth, differentiation, and apoptosis of prostate cancer cells will be identified. Second, the involvement of cAMP-related pathways in RA-induced influences of Cdk5/p35 will be investigated. Third, RA-induced influences on Cdk5/p35-dependent downstream signaling pathways of androgen receptor will be discussed. Forth, cell cycle analysis by flow cytometry was used to verify whether RA-induced change of cell cycle pattern is through the alteration of Cdk5/p35 protein expression and kinase activity. Fifth, investigate whether Cdk5/p35 protein expression and kinase activity are involved in RA-induced changes of growth, differentiation, and apoptosis of xenografted prostate cancer cells in nude mice (pleasec see the scheme for detail). According to our present and expected results (please see the supplemental data), RA possibly causes the differentiation and apoptosis of prostate cancer cells through Cdk5/p35-related signalings and ErbB family might be involved in this pathway. We believe that the contribution of this grant would be helpful to understand the feathure and treatment of prostate cancer.
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