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dc.contributorJung-Yie Kaoen_US
dc.contributor.authorCHUN-CHUAN CHENen_US
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dc.description.abstract多形性膠質母細胞瘤 (glioblastoma multiforme; GBM)屬grade Ⅳ的星狀細胞瘤,為成年人中最惡性的原發性腦瘤,浸潤性高且轉移快速之腦癌。Temozolomide (TMZ)為目前臨床上治療GBM第一線藥物,經抑制DNA 複製而誘發癌細胞死亡,但長期使用TMZ會導致抗藥性之產生。過去研究結果顯示,長期施予TMZ治療GBM易引起connexin43 (Cx43)表現量增加,可能為TMZ造成抗藥性之原因。故本研究欲探討長期給予TMZ治療膠質細胞瘤的抗藥性機制。SRB assay研究結果顯示,給予resistant GBM TMZ藥物治療後,對藥物的感受性降低。Western blot結果顯示resistant GBM的ATP-binding cassette transporters (ABC transporters)相關蛋白不受影響,而是Cx43蛋白表現量明顯增加。隨著給予curcumin濃度與時間增加促使Cx43表現量隨之減少且不影響其他connexin家族蛋白如Cx26與Cx30的表現量,以及EMT (epithelial-mesenchymal transition)相關蛋白如α E-catenin、β-catenin與E-cadherin的表現量。利用SRB和flow cytometer檢測細胞存活情形,結果顯示合併curcumin及TMZ治療GBM後誘發細胞死亡及凋亡現象。Real-time PCR結果顯示curcumin並不影響Cx43 mRNA的表現量,由此發現Cx43蛋白降解可能為轉譯後修飾機制。因此利用translation inhibitor cycloheximide (CHX) 觀察到更促進Cx43的降解,然而給予autophagy inhibitor 3-Methyladenine (3MA) 並沒恢復Cx43的表現量。更重要利用proteasome inhibitor carbobenzoxy-Leu-Leu-leucinal (MG132) 觀察到逆轉curcumin-induced Cx43降解情形。最後合併curcumin和TMZ治療resistant GBM,結果顯示確實造成細胞死亡。因此,Cx43可能為未來治療腦癌之新策略。zh_TW
dc.description.abstractGlioblastoma Multiforme (GBM), the most common adult primary brain tumor, has poor prognosis with < 3% survival after 5 years of diagnosis. Currently, anti-neoplastic treatment combines chemotherapy, temozolomide (TMZ), radiotherapy and resectional surgery. TMZ is an alkylating agent that induces apoptosis through DNA strand breaks is considered as the frontline chemotherapeutic agent for GBM. Despite its frontline status, GBM patients commonly exhibit resistance to TMZ treatment. Therefore, current study intends to investigate the resistant mechanism underlying long term TMZ-treatment GBM. SRB assay showed that GBM cells exhibit resistance to TMZ treatment. Western blot showed that connexin43 overexpression in resistant GBM cells and did not affect the ATP-binding cassette transporters (ABC transporters) expression. Further suggested that curcumin significantly reduced connexin43 protein expressions in time and dosage dependent manners. Furtheremore, curcumin did not affect connexin26, β-catenin, α E-catenin expressions in human GBM. Combined treatment of curcumin and TMZ promotes cell death and apoptosis using SRB assay and flow cytometry. Interestingly, curcumin did not affect connexin43 mRNA expression in human GBM cells. This reaction appears to be mediated by a post-translational modification mechanism. However, treatment with translation inhibitor cycloheximide (CHX) exerts an additional effects of connexin43 degradation. Treatment with autophagy inhibitor 3-Methyladenine (3MA) did not reverse curcumin-induced connexin43 degradation. Importantly, treatment with a proteasome inhibitor carbobenzoxy-Leu-Leu-leucinal (MG132) significantly reversed curcumin-induced connexin43 degradation. Our results suggest that curcumin induces connexin43 degradation through the ubiquitin-proteasome pathway. Current findings suggest that combined treatment of curcumin and TMZ significantly increases resistant GBM cell death and connexin43 can be a potential therapeutic candidate for the treatment of brain cancer.en_US
dc.description.tableofcontents目錄 1 摘要 4 Abstract 5 第一章 緒論 7 前言 7 第一節 研究背景 8 1-1 腦瘤簡介 8 1-2 縫隙連接蛋白(connexin43, Cx43) 10 1-3 帝盟多(temozolomide, TMZ) 14 1-4 薑黃素簡介(curcumin, CUM) 16 第二節 研究目的 19 研究動機 19 第二章 研究方法 33 2-1實驗材料 33 2-2細胞培養(cell culture) 37 2-3細胞計數法(Trypan blue stain) 38 2-4細胞存活率測定(Sulforhodamine B Assay ) 39 2-5西方墨點分析法(western blot analysis ) 40 2-6細胞凋亡的測定(PI/Annexin V Assay) 41 2-7 RNA之抽取(RNA extract) 42 2-7 Real time-PCR (Real time-Polymerase chain reaction) 43 2-8 siRNA轉殖(siRNA transfection) 44 2-9免疫螢光染色(Immunofluorescence) 45 2-10統計分析(Statistics) 45 第三章 研究結果 46 3-1 Cx43表現量增加在人類膠質細胞瘤 46 3-2 polyphenol促進人類膠質細胞瘤Cx43降解 47 3-3 curcumin促進人類膠質細胞瘤Cx43降解 48 3-4 curcumin不影響人類膠質細胞瘤中Cx26, β-catenin, α E-catenin表現量 49 3-5 curcumin促進人類膠質細胞瘤temozolomide (TMZ)誘發細胞死亡 50 3-6合併curcumin 及temozolomide (TMZ)促進人類膠質細胞瘤加成性細 胞凋亡 51 3-7 curcumin不影響人類膠質細胞瘤Cx43 mRNA的表現量 52 3-8 curcumin透過泛素化(ubiquitin-proteasome pathway)降解Cx43 53 3-9 knockdown Cx43促進人類膠質細胞瘤細胞凋亡 55 3-10合併curcumin及temozolomide (TMZ)促進抗藥性人類膠質細胞瘤細 胞死亡 56 第四章 討論與結論 57 圖目錄 2 附圖一 Current World Health Organization (WHO) classifications for diffuse glioma and medulloblastoma. 20 附圖二 Previous studies on connexin expression in human astrocytomas 21 附圖三 Connexin43 and cell growth regulation 22 附圖四 Connexin43 and apoptosis 24 附圖五 PH-dependent conversion of TMZ to metabolites 26 附圖六Schematic of damage, repair, and apoptotic pathways potentially responsible for temozolomide cytotoxicity and resistance 27 附圖七Isolation, extraction, and structure of curcumin 28 附圖八Various cancers against which curcumin has potential for prevention and treatment 29 附圖九Stages in tumor progression inhibited by curcumin. 30 附圖十Molecular targets of curcumin 31 Figure 1 Connexin43 overexpression in resistant GBM cells 58 Figure 2 Polyphenol promotes connexin43 degradation in human GBM cells 60 Figure 3 Curcumin effectively induces connexin43 degradation in human GBM cells 62 Figure 4 Curcumin did not affect connexin26, β-catenin and α E-catenin expression in human GBM cells 64 Figure 5 Curcumin promotes TMZ-induced cell death in human GBM cells. 66 Figure 6 Combined treatment with curcumin and TMZ leads to synergistic effects of cell apoptosis in human GBM cells 68 Figure 7 Curcumin did not affect connexin43 mRNA expression in human GBM cells 70 Figure 8 Curcumin induces connexin43 degradation through the ubiquitin-proteasome pathway 72 Figure 9 knockdown of connexin43 induces cell apoptosis in human GBM cells 74 Figure 10 Combined treatment with curcumin and TMZ enhances resistant GBM cell death 76 參考文獻 78zh_TW
dc.subjectglioblastoma multiformeen_US
dc.titleCurcumin promotes connexin43 degradation and temozolomide-induced glioma cell deathen_US
dc.typeThesis and Dissertationen_US
item.openairetypeThesis and Dissertation-
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