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研究生:蔡淑婷
研究生(外文):Shu-Ting Tsai
論文名稱:丹蔘二萜抑制人類前列腺癌細胞生長、爬行及侵入能力
論文名稱(外文):Danshen diterpenes suppress the growth, migration, and invasion of human prostate cancer cells.
指導教授:高永旭
指導教授(外文):Yung-Hsi Kao
學位類別:碩士
校院名稱:國立中央大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:146
中文關鍵詞:前列腺癌丹蔘二萜生長爬行侵入
外文關鍵詞:prostate cancerdanshen diterpenesgrowthmigrationinvasion
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前列腺癌是老年男性最常見的生殖系統癌症,其發展受到遺傳、生理、營養和中草藥等因素的調節。儘管已經發現丹蔘二萜類(DDs)抑制前列腺癌細胞的生長,但其作用的確切機制仍不清楚,且他們對前列腺癌遷移和侵入能力的作用也不清楚。使用正常前列腺癌上皮細胞RWPE-1、雄性素依賴型前列腺癌細胞LNCaP以及雄性素不依賴型前列腺癌細胞PC-3和DU-145,我們證實了主要丹蔘中主要的五種丹蔘二萜化合物,例如:Cryptotanshinone (CT)、Dihydroisotanshinone I (DHITI)、Dihydrotanshinone I (DHTI)、Tanshinone I (TI)、Tanshinone IIA (TIIA)分別具有不同的抑制正常和癌性人類前列腺癌細胞生長的能力,而在丹蔘純化物中水溶性萃取物中選取Salvianolic acid B(SAB)作為二萜類對照,在丹酚酸 B (SAB)在存活率中沒有作用。進一步使用傷口癒合爬行實驗結果顯示,所有的丹蔘二萜類都劑量依賴性的抑制PC-3和DU-145細胞的爬行,但SAB沒有作用。接著使用基質侵入試驗,我們也發現在經過處理這五種丹蔘二萜後都劑量依賴性的抑制了前列腺癌細胞的侵入能力。一般來說,DHITI和DHTI比其他三個丹蔘二萜類化合物更有效。這說明二萜結構依賴性效應和甲基官能基團的重要性。我們從蛋白質訊號數據中發現,二萜類選擇性誘導AKT、AMPK、p38 MAPK和c-JUN蛋白的磷酸化,而對JNK蛋白的磷酸化沒有影響。二萜類也選擇性抑制基質金屬蛋白酶(MMP-2/-9)的活性,並傾向於抑制上皮-間質轉化(EMT),例如E-cadherin、Zonula occludens蛋白質表現水平升高和降低N-cadherin、Snail-1以及Vimentin等蛋白質表達。丹蔘二萜類也選擇性地對血管內皮因子-B/-D的蛋白質表達具有抑制的作用,並且對缺氧誘導因子-1a和活化轉錄因子(ATF3)蛋白具有抑制作用。這些數據都指出著丹蔘二萜類藉由化學結構、EMT蛋白、MMP蛋白、蛋白激酶級聯級轉錄因子和血管生成因子依賴性,從而抑制前列腺癌細胞生長、爬行以及侵入能力
Prostate cancer (PCa) is the most common cancer of the reproductive system in elderly men and its development can be regulated by genetic, physiological, nutritional, and herbal factors. Although danshen diterpenes (DDs) were found to inhibit the growth of PCa cells, the exact mechanisms of their actions are still not clear and neither are their actions on prostate cancer migration and invasion. Using normal RWPE-1 prostate epithelial cells, androgen-dependent LNCaP PCa cells, and androgen-independent PC-3 and DU-145 PCa cells, we confirmed herein that the major DDs, such as cryptotanshinone (CT), dihydroisotanshinone I (DHITI), dihydrotanshinone I I (DHTI), tanshinone I (TI), and tanshinone IIA (TIIA), had different potencies to suppress growths of normal and cancerous human prostate cells and that salvianolic acid B (SAB) had no effects. Further wound healing migration assay indicated that all the diterpenes, but not SAB, dose-dependently suppressed the migration of PC-3 and DU-145 PCa cells. Using matrigel invasion assay, we also found that all the five diterpenes dose-dependently inhibited prostate cancer cell invasion after the treatment. Generally, DHITI and DHTI were more effective than other three structure-related diterpenes. This suggests the diterpene structure-dependent effect and the importance of methyl functional group. When signaling proteins were examined, diterpenes selectively induced increases in the phosphorylations of AKT, AMPK, p38 MAPK, and c-JUN proteins, inhibited STAT-3 protein phosphorylation, and had no effect on JNK protein phosphorylation. Diterpenes selectively inhibited activities of matrix metalloproteinases (MMP)-2 and -9 and tended to suppress the epithelial-mesenchymal transition (EMT), as indicated by increased levels of E-cadherin, claudin, and zonula occludens-1 proteins and by decreased levels of N-cadherin, Snail, and vimentin proteins. Diterpenes had selectively inhibitory effects on the protein expression of vascular endothelial growth factors B and D, as well as stimulatory effects on hypoxia-inducible factor 1-alpha and activating transcription factor (ATF)-3 proteins. These data suggest that danshen diterpenes suppress prostate cancer cell growth, migration and invasion with chemical structure, EMT protein, MMP protein, protein kinase cascade, transcription factor, and/or angiogenic factor dependencies.
目錄
中文摘要 I
ABSTRACT III
致謝 IV
目錄 VI
縮寫與全名對照表 IX
壹、前言 1
1-1 前列腺癌 1
1-2 上皮間質轉化 (EMT) 3
1-3 丹蔘 5
1-4 研究動機與目的 7
貳、材料與方法 9
2-1 實驗材料 (Experimental materials) 9
2-2 細胞培養 (Cell culture) 9
2-3 細胞存活率實驗 (Cell viability assay) 10
2-4 軟瓊脂集落形成測定 (Soft agar colony formation assay) 10
2-5 傷口癒合爬行測試 (Wound healing migration assay) 12
2-6 細胞侵入分析 (Boyden chamber invasion ssay) 12
2-7 西方墨點法 (Western blot) 13
2-8 酶譜法 (Zymography assay) 16
2-9 統計分析 (Statistical analysis) 18
參、結果 19
3-1 丹蔘二萜類影響正常前列腺上皮細胞與前列腺癌細胞的存活率 19
3-2 丹蔘二萜類抑制雄性素不依賴型前列腺癌細胞的群落形成能力 21
3-3 丹蔘二萜類抑制雄性素不依賴型前列腺癌細胞的爬行能力 22
3-4 丹蔘二萜類抑制雄性素不依賴型前列腺癌細胞的侵入能力 23
3-5 丹蔘二萜類對人類雄性素不依賴性前列腺癌EMT蛋白的影響 24
3-6-1丹蔘二萜類抑制人類雄性素不依賴性前列腺癌基質金屬蛋白質MMP-2、MMP-9活性 26
3-6-2 丹蔘二萜類對人類雄性素不依賴性前列腺癌AMPK的影響 26
3-6-3 丹蔘二萜類對人類雄性素不依賴性前列腺癌Akt的影響 27
3-6-4 丹蔘二萜類對人類雄性素不依賴性前列腺癌MAPK家族蛋白的影響 28
3-6-5 丹蔘二萜類對人類雄性素不依賴性前列腺癌c-JUN的影響 28
3-6-6 丹蔘二萜類對人類雄性素不依賴性前列腺癌ATF3的影響 29
3-6-7 丹蔘二萜類對人類雄性素不依賴性前列腺癌STAT3的影響 30
3-6-8 丹蔘二萜類抑制人類雄性素不依賴性前列腺癌內皮生長因子及缺氧誘導因子 30
肆、討論 32
4-1 丹蔘影響人類雄性素不依賴性前列腺癌細胞的生長及存活率 32
4-2 丹蔘對前列腺癌侵入與轉移的影響 34
4-3 丹蔘在動物和人類藥物劑量的影響 37
4-4未來可以深入進行探討 39
伍、結論 41
陸、參考文獻 43
柒、表目錄 60
捌、圖目錄 71
玖、附錄及補充資料 120
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