臺灣博碩士論文加值系統

膀胱癌為泌尿道腫瘤中發生率最高者。膀胱癌病人經手術及化療藥物治療後，其五年存活率在表淺性腫瘤達90%以上，在局部侵犯者在40-50%；已轉移者則很低。Lovastatin是一種經抑制體內Mevalonate生成而達到降低血脂肪的statin類藥物，近來除廣泛用於治療血脂異常，預防心臟血管疾病外；有諸多研究發現Statin類藥物可抑制腫瘤細胞生長、促進腫瘤細胞Apoptosis的發生、亦可與數種化療藥物(如Doxorubicin)合併使用，以降低化療藥物對身體的傷害或增強化療藥物對於腫瘤的治療效果。在之前研究中發現Ceramide會誘發老鼠膀胱癌細胞MBT-2細胞死亡，其成因為Ceramide誘會發細胞產生代謝壓力，活化細胞內的AMPK，亦會細胞內使Bcl-2 family中Anti-apoptosis Bcl family的Bcl-XL減少、Pro-apoptosis Bcl family的BAD活化，最後使粒線體通透性增加，促使Cytochrome C釋出與外膜電位喪失，但Ceramide對人類膀胱癌細胞T-24細胞卻沒有類似的結果。
本實驗延續前人研究，確認ceramide造成MBT-2細胞死亡的原因及AMPK與BAD活化的關係。實驗結果顯現ceramide會造成MBT-2細胞內AMPK磷酸化及p-BAD去磷酸化，Knock-down BAD可減少ceramide所造成的粒線體外膜電位喪失和細胞死亡。但是在人類T-24細胞並無相同結果，若T-24先以lovastatin 處理後，發現lovastatin可增加ceramide促進細胞死亡的效果，實驗發現單獨使用lovastatin或ceramide處理並不會造成上述效果。進一步加入Mevalonate時，細胞死亡狀況會被抑制。此結果指出ceramide誘發T-24細胞死亡作用和抑制mevalonate pathway有關。另加入AMPK抑制劑Compound C，來觀察AMPK在以ceramide或合併lovastatin處理導致MBT-2、T-24細胞死亡作用是否具有相同重要性。實驗結果發現Compound C會抑制細胞死亡，因此AMPK在此路徑中具重要性。總而言之ceramide誘發MBT-2死亡與AMPK活化、p-BAD去磷酸化導致MBT-2細胞內pro-apoptotic蛋白活化有關，同時lovastatin在ceramide誘導T-24細胞死亡有其重要性。

Lovastatin is a cholesterol-lowering drug, an inhibitor of mevalonate generation, is wildly used in treatment of dyslipidemia and prevention of cardiovascular diseases. In addition, lovastatin can inhibit tumor cells growth and promote tumor cells apoptosis, when it combine with some chemotherapy drugs (such as doxorubicin) to reduce the chemotherapy drug side effects or enhance the antineoplastic effects of chemotherapy drug.
In previous studies, Ceramide was able to induce cell death in MBT-2 mouse bladder cancer cell. Since ceramide will induce cell metabolic stress, it activates AMPK, decreased the expression of anti-apoptosis Bcl family Bcl-XL and increases the expression of Pro-Apoptosis Bcl family BAD, finally increases permeability of mitochondria then induces cytochrome C releasing and mitochondria membrane potential losing. However, in human bladder cancer cells (T-24) were not found similar effects. Now our experiment continues previous studies. Ceramide induced MBT-2 cell death effect was detected AMPK phosphorylation and p-BAD dephosphorylation. Knock-down BAD will induce the decrease of mitochondria membrane potential and cell death by ceramide.
Since the ceramide-induced cell death was not found in T24 human bladder cancer cell, we used lovastatin to improve the effect of ceramide in cell death. After the pretreatment of lovastatin, the ceramide-induced cell death was observed in this cell. Moreover, the cell death was inhibited by addition of mevalonate, indicating that the blockage of mevalonate pathway is essential for the ceramide-induced cell death in T24 cells. Interestingly, combined ceramide with lovastatin was able to induce the activation of AMPK and the loss of mitochondrial membrane permeability, but only adding either ceramide or Lovastatin did not show the effects. Compound C, an AMPK inhibitor, was used to observe whether AMPK has an important role in the treatment of ceramide or combined with lovastatin in the MBT2 and T24 cells respectively. The cell death was inhibited by compound C, showing that AMPK involved ceramide and combined with lovastatin induced cell death. In summary, our study show that ceramide-induced cell death via AMPK activation and p-BAD dephosphorylation to activate the pro-apoptotic protein in MBT2 cells and the co-treatment of lovastatin is essential for the ceramide- induced cell death in T24 cells.

辭謝
摘要..I
Abstract…II
壹、導論..1
一、膀胱癌..1
二、Lovastatin..3
三、Ceramide..5
四、BAD..7
五、AMPK..8
六、研究動機..8
貳、材料與實驗方法..10
一、材料..10
二、實驗方法..13
參、研究結果..20
肆、討論..24
伍、參考文獻..27
陸、附錄..35
柒、補充資料..50

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