Taipei Medical University Institutional Repository:Item 987654321/53523
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    Please use this identifier to cite or link to this item: http://libir.tmu.edu.tw/handle/987654321/53523


    Title: Transient Receptor Potential Vanilloid Type I (TRPV1)於吳茱萸鹼毒殺U87 MG神經膠瘤作用之研究
    Effects of Transient Receptor Potential Vanilloid Type I (TRPV1) on Evodiamine-Induced Cytotoxicity in U87-MG Glioma Cells
    Authors: 侯思穎
    Hou, Sz-Ying
    Contributors: 醫學科學研究所
    Keywords: 惡性膠質細胞瘤;吳茱萸鹼;細胞自噬;細胞凋亡;鈣離子;TRPV1;JNK;Malignant glioma;evodiamine;autophagy;apoptosis;extracellular calcium;TRPV1;JNK
    Date: 2013-06-20
    Issue Date: 2018-11-12 14:10:15 (UTC+8)
    Abstract: 惡性膠質細胞瘤為常見原發性腦瘤，以手術難以完全切除，所以臨床上常併用化學治療。然而抗腫瘤藥物往往昂貴且具副作用，因此近年來科學家致力於研發新抗癌藥物，以期能進一步達到減緩腫瘤惡化，延長病患生命之作用。吳茱萸鹼 (evodiamine) 是由中草藥吳茱萸所萃取出具生物活性之生物鹼，過去已有文獻證實，evodiamine可藉由誘導腫瘤細胞凋亡 (apoptosis)，足見其可能具有抗癌能力，且其分子量為303.3 Daltons，具有通過血腦屏障(Blood-brain barrier，簡稱BBB)的可能性，因此可能為腦瘤之新藥開發提供新方向。文獻證實，evodiamine可誘導癌細胞進行計劃性細胞死亡：包括第一型細胞凋亡(apoptosis)及第二型細胞自噬(autophagy)，但其詳細機制目前仍尚未釐清。鈣離子為二級訊息傳遞分子之一，細胞凋亡過程中可能伴隨細胞內鈣離子濃度上升，過去文獻指出當細胞受到外來刺激時，胞內鈣離子濃度上升會導致autophagy，進而保護細胞免於apoptosis。因此autophagy在細胞死亡中所扮演的角色仍具爭議性，且胞內鈣離子濃度變化於evodiamine抗癌活性的重要性，有待進一步探討。細胞膜陽離子通道蛋白transient receptor potential vanilloid 1 (TRPV1)廣泛分布於感覺神經、上皮細胞、腦部細胞等，涉及痛覺的訊息傳遞等作用，有文獻指出在glioma cell lines中，TRPV1的表現量較一般細胞為高，且其活化會促使鈣離子流入細胞，進而引發autophagy，然而其確切分子機制仍不清楚。Evodiamine為TRPV1之agonist，然而TRPV1於evodiamine導致apoptosis或autophagy之角色仍未完全了解。因此本論文使用evodiamine與特定抑制劑處理人類惡性神經膠質細胞瘤(U87-MG)細胞，併用流式細胞儀及免疫染色技術，探討evodiamine誘導其死亡的分子機制，並檢測TRPV1的重要性。實驗結果顯示， 細胞外鈣離子螯合劑(EGTA)及TRPV1抑制劑capsazepine (CPZ)皆可抑制evodiamine所誘發之細胞內鈣離子濃度上升，並且降低autophagy比例，同時增加細胞凋亡的現象；另外，JNK特定抑制劑SP600125可降低由evodiamine所誘發之autophagy達 22 %，同時伴隨著apoptosis的上升，且CPZ可降低evodiamine導致的JNK活化，顯示evodiamine可使TRPV1活化，增加細胞內鈣離子濃度，並導致autophagy。此研究之執行希望能有助於瞭解evodiamine對抗腦癌細胞之機轉，以期可以此提供臨床上抗癌藥物開發之新方向，增加腦癌患者的存活率。

    Glioblastomas, the most common primary gliomas, are characterized by increased invasion and difficult therapy. Major clinical medicines for treating gliomas merely extend the survival time for a number of months. Therefore, development of new agents against gliomas is important. Evodiamine (Evo) is extracted from Chinese herbal medicine Evodiae fructus, with alkaloids biological activity. It was reported that Evo, having a molecular weight of 303.3 Daltons, could induce apoptosis in tumor cells, suggesting that Evo has an ability to pass through BBB to treat brain cencer. Variation of intracellular calcium concentration may involve in the regulating of apoptosis and autophagy. However, the detail molecular mechanism is not well-understood. Transient receptor potential vanilloid type 1 (TRPV1) receptor, a non-selective ligand-gated cation channel, is widely distributed in the sensory nerve, epithelial cells, and brain cells. The biological function of TRPV1 is transmission and modulation of pain, as well as the integration of diverse painful stimuli. It has been reported that TRPV1 activation may lead to apoptosis in glioma cells, as well as lead to autophagy through calcium-mediated signaling. However, the role of TRPV1 in Evo-induced autophagy is unclear. In this study, we investigated the underlying molecular mechanism of Evo-induced cytotoxicity in glioma cells, using the technique of flow cytometry and immunoblotting. Herein, we found that scavenger of extracellular calcium (EGTA) and inhibitor of TRPV1 (capsazepine, CPZ) reduced EVO-induced increase of [Ca2+]i and autophagy accompanied with increase of apoptosis. Moreover, inactivation of c-Jun N-terminal kinase (JNK) suppressed Evo-mediated autophagy accompanied by increasing apoptosis. Finally, Evo-induced JNK activation was reduced by treatment with CPZ and BAPTA-AM, suggesting Evo-induced JNK-mediated autophagy was resulted from influx of extracellular calcium through TRPV1 channel. Execution of this study will produce a strategy for development of new chemotherapeutic agents against brain cancer. Overall, these findings suggest that Evo-induced a protective autophagy against apoptosis through TRPV1/JNK pathway.
    Description: 碩士
    委員-葉添順
    指導教授-施純明
    委員-馮琮涵
    Data Type: thesis
    Appears in Collections:[Graduate Institute of Medical Sciences] Dissertation/Thesis

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