進階搜尋


 
系統識別號 U0026-2207201415501600
論文名稱(中文) 透過組蛋白去乙醯酶抑制劑SAHA導致自噬作用促使乳癌細胞死亡的分子機制
論文名稱(英文) Mechanistic insight into SAHA-induced autophagic cell death in breast cancer cells
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 102
學期 2
出版年 103
研究生(中文) 李盈潔
研究生(英文) Jane Ying-Chieh Lee
學號 S26015011
學位類別 碩士
語文別 英文
論文頁數 91頁
口試委員 口試委員-張玲
口試委員-陳韻雯
指導教授-張雋曦
中文關鍵字 細胞自噬  存活素  組蛋白去乙醯酶抑制劑 
英文關鍵字 Autophagy  survivin  HDAC inhibitor 
學科別分類
中文摘要 在近幾年的癌症研究中,組蛋白去乙醯酶抑制劑已被證實在許多固體和血液腫瘤中具有抑癌能力,因此被視為具有潛力的癌症治療標靶。其中組蛋白去乙醯酶抑制劑Vorinostat (簡稱SAHA),已被FDA核准於臨床血液腫瘤的治療,並廣泛地投與在其他癌症的療效評估。雖然前人的研究發現SAHA可藉由引發癌細胞自噬作用 (autophagy) 死亡,進而抑制癌細胞增生;然而對於SAHA如何引起自噬作用死亡的機制仍然不明,須進一步研究。因此本篇的研究目的是利用人類乳癌細胞實驗模式,進而深入探討SAHA如何導致自噬細胞作用死亡的詳細機制。

本研究發現廣泛型組蛋白去乙醯酶抑制劑SAHA會造成存活素(survivin) 和XIAP的表現量下降。進一步透過西方墨點法,助溶酶體染料 (Lysotracker) 及單丹(磺)酰戊二胺染色 (MDC staining) 發現,SAHA會引起自噬蛋白 (LC3) 的轉變,並有效促使自噬體與自噬溶酶體的形成。當SAHA與存活素抑制劑YM155或XIAP抑制劑Embelin合併使用時,可以更顯著的降低存活素和XIAP的表現,並增強SAHA細胞自噬能力,進而提高乳癌細胞對於藥物的敏感性。此外,透過siRNA方式來降低survivin的表現量也可觀察到一致的結果。在分子層面,利用逆轉錄聚合酶鏈式法 (RT-PCR) 發現,高濃度的SAHA會抑制存活素的基因轉錄。本研究透過抑制蛋白合成能力亦觀察到,SAHA會經由調控蛋白酶體 (26S proteasome) 及熱休克蛋白 (heat-shock protein 90),進而降低存活素及XIAP蛋白的穩定性。接著以不同的HDAC抑制劑(BML281,MGCD0103,TSA,MC1568) 發現SAHA會藉由HDAC異構物1、2、3、6有效的抑制存活素及XIAP的表現。並且,專一性的siRNA可藉由降低HDAC異構物1-6的表現,發現HDAC 3以及HDAC 6是抑制存活素和XIAP表現的主要因素。

總和上述結果可知,SAHA會經由調控HDAC 3及HDAC 6,促使蛋白酶降解survivin及XIAP,而誘發乳癌細胞的自噬死亡及毒殺作用其中,確認HDAC異構物如何調控抗凋亡蛋白的機制則可提供將來HDAC抑制劑藥物在標靶及合併治療的新穎選擇。
英文摘要 In recent years, histone deacetylase inhibitors (HDACis), a novel class of agents that targets mechanistic abnormalities in cancers, have shown promising anti-cancer activity in both haematological and solid cancers. Among them, SAHA (Vorinostat, a pan-HDACi) is approved by FDA to treat cutaneous T-cell lymphoma and is being evaluated in other cancer types including breast cancer. Although several studies have shown that SAHA exhibits potent anti-proliferative effects and induces autophagic cell death, the exact mechanisms by which SAHA induces autophagic cell death have not been fully understood. Therefore the aim of this study is to investigate the underlying mechanisms of SAHA-induced autophagic cell death in cancer cells.

In our study, we observed that SAHA, a pan-HDAC inhibitor, downregulated the expression of survivin and XIAP in both concentration- and time-dependent manner. Through Western blotting, lysotracker and MDC staining, indunction of LC-3B conversion and autophagosome/autolysosome formations were observed in the cells treated with SAHA. MTT cell viability assay, Western blotting showed that the addition of YM155 and Embelin (survivin and XIAP inhibitor respectively) further depleted survivin and XIAP levels respectively thereby enhancing the autophagic and cytotoxic effects of SAHA in the treated cells. Downregulation of survivin by siRNA also increased the sensitivity of MCF-7 cells to SAHA. At the molecular level, RT-PCR analysis revealed that at high concentration (2xIC50) SAHA inhibited survivin gene transcription. Subsequent protein stability assay and Western blotting showed that SAHA reduced the protein stability of survivin and XIAP possibly through modulating 26S proteasome and heat-shock protein 90. We further performed Western blotting with the addition of various selective HDAC inhibitors (BML281, MGCD0103, TSA and MC1568) where the results showed that HDAC 1, 2, 3 and 6 may be the contributors in SAHA-mediated survivin and XIAP depletion in MCF-7 cells. By specifically silencing HDAC1-6 isoforms with siRNA, we demonstrated that HDAC 3 and HDAC 6 isoforms are the major contributors in suppressing survivin and XIAP in both cancer cells.

Taken together, proteasomal degradation of survivin and XIAP promoted by HDAC 3 and 6 isoforms inhibition might play important roles in the SAHA-induced autophagy and autophagic cell death in breast cancer models. Importantly, identification of how each HDAC isoforms regulate members of IAP family can potentially be applied to predict novel HDACI in targeted or combinational therapies in the future.
論文目次 中文摘要 I
ABSTRACT IV
Acknowledgement VII
Abbreviation IX
List of Tables XII
List of Figures XIII
List of Appendices XV
INTRODUCTION 1
1.1. Breast Cancer 2
1.1.1 The epidemiology of breast cancer 2
1.1.2 Treatments of breast cancer 2
1.1.3 Drug resistance 4
1.2. Chromatin modification and histone deacetylases (HDACs) 4
1.2.1. Genetic and epigenetic alterations in cancer 4
1.2.2. Histone modification 5
1.2.3. Histone deacetylases (HDACs) 6
1.3. HDACs as a target for cancer treatment 7
1.3.1. HDACs and cancer 7
1.3.2. The molecular mechanism and classification of HDAC inhibitors (HDACIs) 8
1.3.3. HDACIs in current clinical use and clinical trials 9
1.3.4. HDACIs in breast cancer 10
1.4. Inhibitor of Apoptosis Proteins (IAPs) 11
1.4.1. IAP family and cancer 11
1.4.2. Functions of survivin and XIAP 13
1.4.3. HDAC and survivin/XIAP 13
1.5. Aims of this study 15
MATERIALS AND METHODS 16
2.1. Materials 17
2.2. Recipes 20
2.3. Methods 22
2.3.1. Cells and culture 22
2.3.2. MTT assay 23
2.3.3 Western blot analysis 23
2.3.4. MDC staining 24
2.3.5. Lysotracker Red staining 24
2.3.6. RNA extraction and reverse-transcriptase PCR (RT-PCR) assays 25
2.3.7. Proteasome activity Assay 25
2.3.8. Gene silencing by siRNA 26
2.3.9 Protein stability Assay 26
2.3.10 Plasmids 27
2.3.11 Electroporation 27
2.3.12 Cell fractionation Assay 27
2.3.13 Statistic analysis 28
RESULTS 29
3.1. SAHA treatment induces autophagy and in human breast cancer cells. 30
3.2. Downregulation of survivin and XIAP induces LC3B-II conversion in human breast cancer cells. 31
3.3. Downregulation of survivin and XIAP increased the sensitivity of human breast cancer cells to SAHA. 32
3.4. SAHA treatment reduces the protein stability of survivin and XIAP in human breast cancer cells. 33
3.5. SAHA treatment promotes proteasomal degradation of survivin and XIAP in human breast cancer cells. 34
3.6. HDAC 3 and HDAC6 isoforms are the possible contributors in SAHA-mediated survivin and XIAP depletion in human breast cancer cells. 36
DISCUSSION & 38
CONCLUSIONS 38
4.1. Discussion 39
4.2. Conclusions 45
REFERENCES 46
TABLES 60
FIGURES 64
APPENDICES 84
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