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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22516Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 鄧哲明 | |
| dc.contributor.author | Yu-Wei Chang | en |
| dc.contributor.author | 張佑維 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:19:41Z | - |
| dc.date.copyright | 2010-09-13 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-07-21 | |
| dc.identifier.citation | Abelev GI (1968) Production of embryonal serum alpha-globulin by hepatomas: review of experimental and clinical data. Cancer Res 28, 1344-1350.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22516 | - |
| dc.description.abstract | 最近幾年的研究中發現， digitalis 和 digoxin 這類強心配醣體類藥物有對抗癌細胞生長之作用，因此具有發展成為抗癌藥物的研究潛力。肝癌 (hepatocellular carcinoma, HCC) 因為往往對現今化療藥物會發生阻抗性，使其癒後相當不好，也成為近幾年來台灣肝癌病患高死亡率的原因之一。因此，治療肝癌的小分子藥物一直是世界各國大藥廠積極研究開發之對象。Lanatoside C 是從毛地黃Digitalis lanata 所萃取出來的，過去曾用於治療心律不整。Lanatoside C 對於 HCC 的細胞株 Hep3B (GI50 = 1.4 × 10-7 M) 和 HA22T (GI50 = 1.2 × 10-7 M) 具有抑制生長的能力。Hep3B 細胞給予 lanatoside C 後，會大部分進入 subG1 phase，並藉由 TUNEL 試驗證實為細胞凋亡的反應。Lanatoside C 會活化 caspase-8 並藉由 Bcl-2 家族蛋白： BID 的 proform、 Bcl-xL 和 Mcl-1 的減少，進一步引起粒線體膜電位 (mitochondrial membrane potential, MMP) 下降。MMP 下降後，Lanatoside C 活化 caspase-9 並促使 apoptosis inducing factor (AIF) 進入細胞核內。因此，Lanatoside C 在 Hep3B 細胞中能分別透過 caspase-dependent 路徑與 caspase-independent 路徑來調控細胞凋亡。本篇實驗首先發現 lanatoside C 能藉由磷酸化 PKCδ Thr505 與使 PKCδ translocate 到細胞膜上而活化 PKCδ。於是，利用rottlerin (PKCδ 專一性抑制劑) 發現能回復 lanatoside C 造成的 MMP 下降與細胞凋亡，也會回復 Bcl-2 家族蛋白表現量減少 (Mcl-1 和 BID)、 caspase-3、 caspase-8 活化和 AIF 進入細胞核等現象，這個結果確認 lanatoside C 會藉由活化 PKCδ 而調控細胞凋亡。此外，我們發現在 Hep3B 細胞中，lanatoside C 能抑制 ERK1/2 的磷酸化與 AKT / mTOR 路徑的磷酸化表現；進一步將 MEK 和AKT overexpression，能部分回復 lanatoside C 引起的細胞凋亡，此結果說明 lanatoside C 抑制 ERK1/2 與 AKT 的磷酸化會部分參與在 lanatoside C 造成的細胞凋亡反應之中。接著在合併處理rottlerin 後，能回復 lanatoside C 抑制的 AKT / mTOR 路徑磷酸化；但卻不影響 ERK1/2 的磷酸化。因此認為 lanatoside C 能經由 PKCδ 活化而負向調控 AKT / mTOR 路徑的磷酸化表現。在本實驗中首先證實 lanatoside C 在人類肝細胞癌 Hep3B 細胞所引起的細胞凋亡主要藉由 PKCδ 所調控。 | zh_TW |
| dc.description.abstract | Recent studies revealed that cardiac glycosides, such as digitalis and digoxin,have anticancer activity and may serve as lead compounds developed for cancer treatment. Hepatocellular carcinoma (HCC) is one of the most common causes of deaths in Taiwan. The poor prognosis of HCC is due to the high resistance to current chemotherapeutic agents and, therefore, new small-molecule agents still need to be discovered. Lanatoside C, extracted from Digitalis lanata, is an anti-arrhythmic agent. We found that anatoside C showed a growth inhibition in HCC Hep3B cells (GI50 = 1.2 × 10-7 M) and HA22T cells (GI50 = 1.4 × 10-7 M). After lanatoside C treatment,the cell cycle distribution of Hep3B cells shifted to subG1 phase and the positive results of TUNEL staining represented Hep3B cells undergoing apoptosis. Lanatoside C triggered caspase-8 activation and mitochondrial membrane potential (MMP) loss which was caused by downregulating the anti-apoptotic Bcl-2 family protein, proform of BID, Mcl-1 and Bcl-xL. After MMP loss, lanatoside C caused caspase-9 activation and triggered apoptosis inducing factor (AIF) translocation into the nucleus. Therefore, lanatoside C induced Hep3B cell apoptosis through caspase-dependent and caspase-independent pathways. We first discovered that lanatoside C activated protein kinase C delta (PKCδ) through Thr505 phosphorylation and subsequent membrane translocation. Therefore, we used rottlerin, a specific PKCδ inhibitor to reverse lanatoside C-induced MMP loss and apoptosis in Hep3B cells. Rottlerin diminished lanatoside C-induced apoptotic signaling such as Bcl-2 family protein (Mcl-1 and
BID) downregulation, caspase-3 and caspase-8 activation as well as AIF nuclear translocation. These results confirmed lanatoside C- induced apoptosis through PKCδ activation. Furthermore, we demonstrated that lanatoside C inhibited phosphorylation of ERK1/2 and AKT/mTOR pathway in Hep3B cells. Overexpression of MEK and AKT partially reversed lanatoside C-induced apoptosis. These results indicated that lanatoside C-inhibited phosphorylation of ERK1/2 and AKT partially participated in lanatoside C-induced apoptosis. In addition, rottlerin reversed lanatoside C-inhibited phosphorylation of AKT/mTOR pathway instead of ERK1/2. We suggested that lanatoside C negatively regulated AKT/mTOR pathway phosphorylation through PKCδ activation. In this paper, we first show lanatoside C induces apoptosis of human hepatocellular carcinoma Hep3B cells mainly through PKCδ activation pathway. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:19:41Z (GMT). No. of bitstreams: 1 ntu-99-R97443004-1.pdf: 2948423 bytes, checksum: 3f6a7ef68d72613494e60103ad5f9dea (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 縮寫表 …………………………………………… 1
中文摘要 ………………………………………… 2 英文摘要 ………………………………………… 4 第一章、研究動機與目的 ………………………… 6 第二章、文獻回顧與探討 ………………………… 8 第三章、實驗材料與方法 ………………………… 41 第四章、結果 ……………………………………… 49 第五章、討論 ……………………………………… 54 第六章、結論與未來展望 ………………………… 61 參考文獻 ………………………………………… 80 著作 ……………………………………………… 97 | |
| dc.language.iso | zh-TW | |
| dc.subject | 肝癌 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | PKC delta | en |
| dc.subject | lanatoside c | en |
| dc.subject | hepatocellular carcinoma | en |
| dc.title | Lanatoside C 藉由protein kinase Cδ 促使人類肝癌細胞凋亡機轉探討 | zh_TW |
| dc.title | Lanatoside C causes apoptosis of human hepatocellular carcinoma cell through protein kinase Cδ-dependent manner | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顏茂雄,楊春茂,黃德富,潘秀玲,顧記華 | |
| dc.subject.keyword | 細胞凋亡,肝癌, | zh_TW |
| dc.subject.keyword | lanatoside c,hepatocellular carcinoma,PKC delta, | en |
| dc.relation.page | 97 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2010-07-21 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| Appears in Collections: | 藥理學科所 | |
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|---|---|---|---|
| ntu-99-1.pdf Restricted Access | 2.88 MB | Adobe PDF |
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