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系統識別號 U0026-2406201017101700
論文名稱(中文) 探討尼古丁促進膀胱癌細胞生長與化療抗性的機轉並研究紫檀芪對化療敏感性與尼古丁誘發具化療抗性的膀胱癌細胞之治療效果與機制
論文名稱(英文) The proliferative/chemoresistant effects of nicotine in human bladder cancer cells and the anti-cancer effects of pterostilbene in sensitive and chemoresistant bladder cancer cells
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 98
學期 2
出版年 99
研究生(中文) 陳容甄
研究生(英文) Rong-Jane Chen
學號 s7891103
學位類別 博士
語文別 中文
論文頁數 110頁
口試委員 指導教授-王應然
口試委員-郭浩然
口試委員-潘敏雄
口試委員-何其儻
口試委員-何元順
口試委員-吳梨華
中文關鍵字 尼古丁  紫檀芪  化療抗性  細胞自我吞噬作用  膀胱癌細胞 
英文關鍵字 nicotine  pterostilbene  chemoresistance  autophagy  bladder cancer cells 
學科別分類
中文摘要 香菸是導致膀胱癌發生的主要危險因子,並使膀胱癌病人接受化療時產生化療抗性。香菸中的主要成分尼古丁可以在吸煙者的尿液中被偵測出。已有研究指出尼古丁是造成肺癌的一個共同致癌物質,主要是調控促進細胞生長的路徑,並經由抑制細胞凋亡路徑使癌細胞產生化療抗性。但尼古丁造成膀胱癌細胞增生及化療抗性的機轉仍不清楚。本研究主要的目的是探討尼古丁促進膀胱癌細胞生長與化療抗性的分子機轉,並研究紫檀芪對化療敏感性與尼古丁誘發具化療抗性的膀胱癌細胞之治療效果。
我們發現膀胱癌細胞(T24細胞株)短暫暴露尼古丁之後活化Stat3/ERK1/2路徑,增進Stat3及NF-κB與DNA (去氧核醣核酸)結合能力,進而增加cyclin D1蛋白表現以及細胞增生。本研究中具化療抗性的膀胱癌細胞株(Nic-T24 cells, T24R cells)是由持續處理尼古丁的T24細胞建立的。經由長期處理尼古丁,更活化了Stat3路徑而促進cyclin D1過度表現,細胞週期受到干擾使細胞產生化療抗性。我們發現尼古丁促進細胞增生以及化療抗性的主要機制,是透過活化尼古丁受器或β型交感神經受體,造成Stat3及其下游路徑活化。
我們接著發現紫檀芪對化療敏感及尼古丁誘發具化療抗性的膀胱癌細胞具有治療效果。主要是活化細胞壞死、細胞週期停滯、細胞自我吞噬,及細胞凋亡等路徑。紫檀芪能夠藉由抑制AKT/mTOR/p70S6K路徑,以及活化ERK1/2路徑造成細胞自我吞噬作用,合併使用細胞自我吞噬的抑制劑或是針對ERK1/2及Beclin1設計的小髮夾RNA則會促進細胞凋亡產生。
本研究是第一個探討尼古丁促進膀胱癌細胞增生及化療抗性的研究,長期暴露於尼古丁會造成不良的健康效應,包括膀胱癌的發生以及產生化療抗性。本研究也是第一個發現紫檀芪能夠造成癌細胞發生細胞自我吞噬作用,並能夠用來治療化療敏感及尼古丁誘發具化療抗性的膀胱癌。
英文摘要 Cigarette smoke is a major risk factor for bladder cancer and contributes to chemoresistance in bladder cancer patients who continue to smoke while receiving chemotherapy. The main component in cigarette smoke, nicotine, can be detected in the urine of smoker’s. Nicotine has been implicated as a co-carcinogen that promotes lung cancer development through pro-survival pathways and is known to induce chemoresistance in some cancer cells through anti-apoptosis mechanisms. The molecular mechanism of nicotine’s action in bladder cancer cells proliferation and chemoresistance remain unclear. The aims of our study were to investigate the role of nicotine in inducing bladder cancer cells proliferation and chemoresistance, to identify the signaling transduction pathway regulated by nicotine, and further study the anti-cancer effects of pterostilbene in chemosensitive and nicotine-induced chemoresistant bladder cancer cells.
We found that transient nicotine stimulation activates Stat3/ERK1/2 leading to induction of Stat3 and NF-κB DNA binding activity, which is associated with cyclin D1 expression and cell proliferation in bladder cancer cell line T24 cells. Chemoresistant T24 cells (Nic-T24 cells, T24R cells) used in our study were established by persistent nicotine treatment. We provide evidence that chronic nicotine exposure strongly activated Stat3 leading to cyclin D1 overexpression, cell cycle perturbations, and chemoresistance. Nicotine mobilized cell proliferation/chemoresistance is mainly mediated by Stat3 and its downstream signals via nicotinic acetylcholine receptor or β-adrenoceptor.
We further found that pterostilbene effectively inhibits the growth of sensitive and nicotine-induced chemoresistant human bladder cancer cells by inducing necrosis, cell cycle arrest, autophagy and apoptosis. Pterostilbene-induced autophagy was triggered by the inhibition of AKT/mTOR/p70S6K pathway and activation of ERK1/2 pathway. Inhibition of autophagy by pretreatment with autophagy inhibitors or short hairpin RNAs targeting ERK1/2 or Beclin1 enhanced pterostilbene-triggered apoptosis.
This is the first study to investigate signaling effects of nicotine inducing proliferation and chemoresistance in bladder cells. We suggest that people exposed to nicotine could be at risk for potential deleterious effects, including bladder cancer development and chemoresistance. This is also the first study to demonstrate that pterostilbene causes autophagy in cancer cells and suggests that pterostilbene could serve as a new and promising agent for the treatment of sensitive and nicotine-induced chemoresistant bladder cancer cells.
論文目次 博士論文口試合格證明 I
中文摘要 II
Abstract III
致謝 V
Abbreviations X
Publication list XI
Introduction 1
Cigarette smoke and bladder cancer 1
Nicotine regulated signals 3
Stat3 in cancer biology 6
Role of cyclin D1 in tumor cell proliferation and anti-apoptosis 9
Apoptosis and autophagy 10
Anticancer effects of Pterostilbene 15
Objectives 17
Materials and Methods 18
Materials 18
Cell Culture 19
Pharmacological Treatments and Established the Chemoresistant T24 Cells 19
Trypan blue exclusion assay 20
BrdU incorporation assay 20
MTT assay 21
Immunoblotting and Immunoprecipitation 21
Electrophoretic Mobility Shift Assay 21
Determination of Adrenalin and EGF Levels 22
Determination of Noradrenalin Level 22
Assessment of Apoptosis 22
- Annexin V Staining Assay: 23
- Flow Cytometry Analysis: 23
- Caspase Activity Assay: 23
- DAPI Stain: 23
Annexin V and PI double staining assay 24
Cell cycle analysis 24
Detection and quantification of acidic vesicular organelles with acridine orange staining 24
Electron microscopy 25
RNA interference (RNAi) 25
Transfection of active-form Stat3 26
Statistical Analysis 26
Results 27
Part 1. Rapid Activation of Stat3 and ERK1/2 by Nicotine Modulates Cell Proliferation in Human Bladder Cancer Cells 27
Part 1. Study Design: 27
1.1 Expression of nAChR subunits in bladder cancer cells and effect of nicotine on cell proliferation 28
1.2 Effects of nicotine on cell survival-related and cell cycle regulatory proteins 29
1.3 Effect of nicotine on mitogenic signaling 29
1.4 Blockade of -Adrenoceptors and nAChRs abrogated mitogenic signals activated by nicotine 30
1.5 Cross talk between ERK1/2 and Stat3 signaling pathways in response to nicotine 30
1.6 Proliferation of T24 cells by nicotine stimulation is mediated by nAChR and -adrenoceptors 31
1.7 Effect of NF-κB and Stat3 transcriptional activity on cyclin D1 expression after nicotine treatment 32
Part 2. Long-term Nicotine Exposure-Induced Chemoresistance is Mediated by Activation of Stat3 and Downregulation of ERK1/2 via nAChR and beta-AR in Human Bladder Cancer Cells 34
Part 2. Study Design: 34
2.1 Growth properties of T24 cells with long-term nicotine exposure 35
2.2 Long-term nicotine treatment induces higher chemoresistance in Nic-T24 cells 35
2.3 Overactivation of Stat3 and downregulation of ERK1/2 in chemoresistant Nic-p80 cells 36
2.4 ERK1/2 activation mediates apoptotic cell death induced by anti-tumor agents 37
2.5 Activation of Stat3 and deregulation of ERK1/2 after long-term nicotine exposure is mediated by nAChR and -adrenoceptors 39
Part 3. Pterostilbene Induces Autophagy and Apoptosis in Sensitive and Chemoresistant Human Bladder Cancer Cells 41
Part 3. Study Design: 41
3.1 Pterostilbene inhibits growth in bladder cancer cell lines 41
3.1 Pterostilbene inhibits growth in bladder cancer cell lines 42
3.2 Pterostilbene induces changes in cell cycle distribution and apoptosis in T24 and T24R cells 42
3.3 Pterostilbene induces autophagy in bladder cancer cells 44
3.4 Autophagy inhibitors increased pterostilbene-induced apoptosis in human bladder cancer cells 45
3.5 Pterostilbene induces autophagy through inhibition of the AKT/mTOR/p70S6K pathway and activation of the MEK/ERK1/2 pathway in T24 cells 46
Discussion 48
References 62
Figures 79
Supplementary Data 101
Appendix 1 104
Appendix 2 105
Appendix 3 106
Appendix 4 107
Appendix 5 108
Appendix 6 109
Appendix 7 110

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