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dc.contributor.authorLi, Guan-Shiunen_US
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dc.description.abstract抑制細胞週期是治療惡性腫瘤的研究方向之一。細胞周期受細胞周期依賴型蛋白(Cyclin dependent kinase family, CDK family)所調控,而Roscovitine為CDK family的抑制劑,其中抗腫瘤藥物R-Roscovitine (Seliciclib, CYC202)已進入phase II 臨床試驗階段。在CDK family中, Cdk5對roscovitine的IC50低於其他成員,表示roscovitine對Cdk5的抑制效果最好。Cdk5最早在神經系統中發現並進行研究,一般認為Cdk5不具有調控細胞周期的能力。除了Cdk5,Roscovitine也能抑制Cdk1,並進而導致細胞周期停在G2 / M phase (G2 / M arrest)。在腫瘤細胞的研究指出,經過Roscovitine的處理會抑制及乳癌細胞株的細胞生長。本篇論文主要是將roscovitine應用於攝護腺癌細胞,觀察攝護腺癌細胞對於不同濃度的roscovitine的反應,均可發現細胞生長抑制的情形,進一步分析細胞周期的分布,發現低劑量的Roscovitine處理不會發生G2 / M arrest,於是我們進一步觀察被認為是Cdk5的訊息傳遞及轉錄因子3 (signal transducer and activator of transcription 3, STAT3) Ser727的磷酸化,結果顯示隨著roscovitine的處理,STAT3 Ser727的磷酸化有下降的趨勢。由以上的結果我們認為roscovitine的作用很可能是經由抑制攝護腺癌細胞中Cdk5蛋白活性而產生對細胞的影響,於是我們利用22Rv1細胞株建立活體動物腫瘤生長模型並以活體細胞轉染shRNA抑制Cdk5,發現抑制Cdk5表現的確影響腫瘤的生長。綜合以上離體與活體研究結果,我們認為,Roscovitine有可能透過抑制Cdk5,降低STAT3 S727的磷酸化,調控攝護腺癌細胞的生長。zh_TW
dc.description.abstractInhibition of cyclin-dependent kinases (CDKs) has recently emerged as an interesting approach to treat human malignancies. Roscovitine is well known as CDKs inhibitor and the R-isomer of roscovitine (Seliciclib, CYC202) is currently in phase II clinical trials as an anti-cancer agent. Cdk5 is the most sensitive kinase to roscovitine in CDK family due to the lowest IC50 value although Cdk5 does not contain ability to modulate cell cycle. Besides, our previous results demonstrated that Cdk5 play important roles in supporting proliferation of thyroid cancer cells. In addition to Cdk5, roscovitine could also affect Cdk1 activity to promote G2/M phase arrest. Our current data indicated that relative low concentration of roscovitine induced growth inhibition of prostate cancer cells (LNCaP, PC3, DU145, and 22RV1) without G2/M arrest, which suggests roscovitine might execute the inhibitory effects through non-Cdk1 inhibition and Cdk5 was possibly the main target in our experimental condition. Furthermore, STAT3 phosphorylation at serine residue Ser 727 was reported as a target of Cdk5 kinase and beneficial to cell proliferation. We found that roscovitine could decrease phopho-Ser727 of STAT3 in prostate caner cells. Finally we set up a 22Rv1 tumor modal. We knock down CDK5 expression by turmal shRNA transfection,and found tumor growth slower than control. This result indicated Cdk5 involved in Tumor growth. In conclusion, our results indicate that inhibitory effects of roscovitine on proliferation of prostate cancer cells were at least through inhibition of Cdk5/STAT3 pathway.en_US
dc.description.tableofcontents一. 文獻探討 (一) 攝護腺介紹 1 (二) 攝護腺癌 2 (三) 細胞周期素依賴型蛋白 (Cdk family) 4 (四) 細胞周期素依賴型蛋白抑制劑 6 (五) 第五型細胞周期素依賴型蛋白(Cyclin-dependent kinase 5, Cdk5) 7 (六) Signal transducer and activators of transcription 3, STAT3 12 (七) 本論文的研究動機與目的 14 二. 實驗材料 (一) 細胞株 15 (二) Roscovitine 15 (三) in-vivo jetPEI 16 (四) shRNA 17 (五) 實驗動物 17 (六) 抗體 18 (七) 儀器 18 三. 實驗方法 (一) 細胞培養 1. 培養基配製 20 2. 繼代培養 20 3. 細胞株冷凍與解凍 21 (二) 細胞生長曲線 21 (三) 細胞周期分析 22 (四) 西方墨點法 22 (五) 動物實驗 1. 細胞異種接種 (Xenograft) 23 2. 動物麻醉 24 3 活體腫瘤轉染 25 4 腫瘤大小測定與記錄 27 5 小鼠犧牲與腫瘤取出 27 6 腫瘤石蠟切片 27 四. 實驗結果 (一) Roscovitine抑制攝護腺癌細胞株的增生 29 (二) Roscovitine造成細胞周期中止 29 (三) Roscovitine抑制STAT3 Ser727的磷酸化 30 (四) Roscovitine可抑制裸鼠皮下攝護腺癌腫瘤生長 30 (五) 降低腫瘤中Cdk5的表現會抑制腫瘤生長 31 五. 討論 (一) Cdk family 抑制劑與抗癌藥物研究 33 (二) Cdk5與攝護腺癌的生長 33 (三) 未來研究方向 34 六. 參考文獻 37 七. 圖表 42zh_TW
dc.subjectProstate canceren_US
dc.subjectCyclin-dependent kinase 5en_US
dc.titleCdk5 might be involved in Roscovitine-reduced proliferation of prostate cancer cellsen_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.fulltextno fulltext-
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