臺灣博碩士論文加值系統

本研究室先前證實市售生鮮文蛤 (Meretrix lusoria) 於100℃，30分鐘之萃取液，經30-50% 硫酸銨分劃後所得萃取物 (WG30-50) 對人類融合瘤細胞株HB4C5具有促進增生能力，但對人類肝癌細胞株HuH-6KK及Hep G2則有致死的作用。進一步將WG30-50經Phenyl-TOYOPEARL、Hydroxyapatite、FPLC Superdex 75管柱層析分劃後，發現文蛤萃取物促進HB4C5細胞增生及抑制肝癌細胞生長的成份分別屬於不同分劃。經由螢光染色及DNA片段化分析發現，Superdex 75分離所得第二波峰 (S75II) 會以時間及劑量依存性效果誘導人類肝癌細胞 (HuH-6KK)、人類大腸結腸癌細胞 (HT-29、SK-CO-1、COLO-201)、乳癌細胞 (MCF-7)、子宮頸癌細胞 (HeLa)、巨噬細胞 (U937、J774.1、CCRF-CEM)、老鼠黑色腫瘤細胞 (B16) 等細胞凋亡。S75II以時間及劑量依存性活化caspase-3而誘導HuH-6KK及HT-29細胞凋亡，顯示文蛤萃取物誘導癌細胞凋亡的過程會透過活化細胞內caspase家族。其中在兩株人類巨噬細胞U937和UM之間的耐受性上有很大差異 (賴，2000)。本研究更深入探討文蛤熱水萃取物對兩株細胞株在抗癌活性上之比較，進而了解其抗腫瘤機制。以MTT和LDH分別用來偵測細胞存活率和細胞毒性；探討細胞凋亡方面，利用DNA片段化、propidium iodide (PI) 染色和FACscan流式細胞儀分析來分析S75II對於兩株人類巨噬細胞U937和U937衍生而來的UM的影響。結果發現，S75II只對U937細胞以時間和劑量依存性造成細胞毒性並且誘導細胞凋亡，然而對UM卻不影響，基於兩株細胞在細胞膜結構上有明顯差異，推測可能原因是S75II無法對high mannose的UM造成毒性，以細胞膜加糖鏈抑制試驗加以佐證。U937細胞先以-mannosidase-II抑制劑swainsonine (1 g/ml) 處理五天後，再添加WG30-50測試，結果發現WG30-50對U937致死作用消失，顯示膜結構改變能夠抑制WG30-50之細胞毒性﹔在洋菜電泳膠上觀察不到DNA片段化；以FACscan流式細胞儀分析處於sub-G1期的細胞百分比，結果顯示未處理組隨著WG30-50劑量增加，由10.8%上升至60.8%，然而在處理組並無明顯變動，顯示膜結構改變能夠抑制WG30-50誘導細胞凋亡之能力，使其下降了約75% 凋亡率。為了更加證實是膜結構改變導致WG30-50無法作用，將處理抑制劑達三天的細胞，移除掉抑制劑以新鮮培養基取代培養兩天後，再給予WG30-50處理。結果發現恢復膜結構時又可觀察到WG30-50誘導細胞凋亡現象；以glycosidase I和II抑制劑castanospermine也得到相同的結果。在紅血球凝集試驗，發現WG30-50對綿羊紅血球具有明顯凝集活性且凝集效果與刀豆素concanavalin A (Con A) 相當﹔經總含糖量分析發現WG30-50的含糖量與蛋白質之比值為11.4%，顯示WG30-50是屬於一醣蛋白的凝集素。在熱安定性方面發現，經長期儲存在4oC 之WG30-50移至37oC下處理三天造成分子量約16 kDa蛋白帶明顯消失，且抗癌活性隨處理時間延長而降低，推測此蛋白極可能為其抗癌決定因子。分別添加四種不同的蛋白抑制劑與WG30-50作用仍無法抑制WG30-50在37oC下時所引發的失活現象，意指在37oC下WG30-50並非因酵素性作用導致失活。另外，在高溫100oC和121oC下，發現大多蛋白產生裂解，顯示WG30-50不具熱安定性。
綜合以上研究，證實文蛤熱水萃取物醣蛋白中含有凝集素成份，透過與細胞膜上對swainsonine和castanospermine敏感之糖基作用造成細胞凋亡。

Previous studies demonstracted that the precipitate of 0.3 to 0.5 ammonium sulfate saturation (WG30-50) from hot water extract of fresh hard clam showed not only immune bioactivity but also antitumor activity. After partially purified by Phenyl-TOYOPEARL, Hydroxyapatite, FPLC Superdex 75 and Mono Q chromatography, we found that the growth-promoting and -inhibiting fractions toward HB4C5 and HuH-6KK were different. DNA fragmentation and propidium iodide (PI) stain provided evidences that the Superdex 75 second fraction (S75II) induced apoptosis in hepatoma (HuH-6KK), colon cancer (HT-29, COLO-201 and SK-CO-1), breast cancer (MCF-7), cervix cancer (HeLa), monocyte /macrophage-like cells (U937, J774.1 and CCRF-CEM) and mouse melanoma B16, but not Hep 3B or HL-60. It was interesting that WG30-50 induced DNA fragmentation as an increased in the percent of U937 cells with hypodiploid DNA content by dose- and time-dependent response, but not in UMcells. The UMcells were established from a histiocytic lymphoma cell line, U937 in serum-free medium plus 12-O-tetradecanoyl phorbol 13-acetate (TPA) (Kong et al., 1990). Based on the differences between the surfaces of two cells that provided us a new ideal to identify the molecular mechanism of WG30-50-induced apoptosis. Swainsonine (SW) and castanospermine (CAS) inhibited mannosidase II and glycosidase I and II in N-linked oligosaccharide processing, respectively. Both SW and CAS treatment significantly abrogated WG30-50-induced U937 cells death. WG30-50-induced apoptosis in U937 was reversed by replaced SW by fresh medium cultured for another two days after SW primed the cells for three days. These results indicate that cell N-glycans participate in WG30-50-induced apoptosis. In agglutination assay, WG30-50 has strong agglutinating activity with sheep red blood cells as concanavalin A (Con A). The WG30-50 was irreversibly inactivated during exposure to 37oC for three days. We also found that 16 kDa protein band disappeared in SDS-PAGE. It may be a determinting factor when WG30-50 was treated at 37oC. Four protease inhibitors (pepstain A, leupeptin, aprotinin and phenylmethylsulphonyl fluoride (PMSF)) did not inhitited inactivation of WG30-50 during exposure to 37oC for three days. At high temperatures for a short period of time, WG30-50 was fully broken to small component, and became inactive. Our results indicate that the principle of Meretrix lusoria was a lectin component, and its apoptotic effect was mediated by SW- and CAS-sensitivity of glycosyl-moiety in cell membrane.

中文摘要I
英文摘要III
壹、前言1
貳、文獻整理3
一、食品生理活性物質3
二、魚貝類的生理活性研究5
三、凝集素7
1.凝集素之生理功能與應用7
2.醣蛋白之生化合成及生理意義8
3.凝集素之消化與吸收8
4.細胞對凝集素的胞飲作用9
5.凝集素與細胞凋亡之關係10
四、細胞凋亡12
1.細胞凋亡與壞死的區別12
2.誘導細胞凋亡的相關機制13
2-1.Bcl-2家族13
2-2.NF-kB家族14
2-3.Fas (APO-1, CD95)15
2-4.Protein tyrosine kinase15
2-5.Protein kinase C15
3.介白素1-b轉化家族16
4.腫瘤抑制基因與細胞凋亡17
5.粒線體與細胞凋亡17
參、材料與方法19
一、實驗材料19
1.細胞株19
2.文蛤來源19
3.藥品19
3-1.文蛤之萃取19
3-2.動物細胞培養19
3-3.蛋白質定量20
3-4.總含糖量分析20
3-5.細胞存活率之測定20
3-6.細胞膜毒胞性之測試20
3-7.文蛤抗腫瘤因子之純化20
3-8.凝血活性測定21
3-9.文蛤萃取物熱安定性21
3-10.DNA片段化測定21
3-11.DNA片段化百分比22
3-12.螢光染色法23
4.設備23
二、實驗方法24
1.細胞培養24
1-1. 懸浮性細胞培養24
1-2. 附著性細胞之培養25
2.文蛤熱水萃取物之製備25
3.蛋白質定量25
4.總含糖量分析26
5.細胞存活率26
6.細胞膜毒胞性之測試26
7.膠電泳分析27
8.醣蛋白鑑別29
9.胺基酸組成分析29
10.N-端胺基酸序列定序30
11.凝血活性測定30
11-1. 凝血活性分析30
11-2. 醣類抑制凝集活性測試30
12.細胞膜加糖鏈之抑制測試31
13.文蛤萃取物熱安定性31
14.市售凝集素對細胞生長之影響31
15.常見誘導細胞凋亡劑對細胞生長之影響32
16.細胞凋亡之測定32
16-1.DNA片段化測定32
16-2.DNA片段化百分比32
16-3.細胞週期分析33
17.統計方法33
肆、結果與討論34
一、不同產地及月份之文蛤熱水萃取物抗癌活性之比較34
二、文蛤萃取物對人類巨噬細胞株U937及UMF生長之影響35
三、細胞膜加糖鏈抑制劑對文蛤萃取物誘導細胞凋亡之影響36
1.Swainsonine細胞膜加糖鏈抑制測試37
2.Castanospermine細胞膜加糖鏈抑制測試41
四、文蛤萃取物對紅血球凝集活性42
五、文蛤萃取物熱安定性43
六、文蛤萃取物之定序及氨基酸組成分析45
七、市售凝集素對人類巨噬細胞株U937及UMF生長之影響45
八、不同細胞凋亡誘導劑對人類巨噬細胞株U937及UMF生長之影響46
伍、結論47
陸、參考文獻51
柒、圖表63

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