博碩士論文 992404004 詳細資訊



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姓名 霍捷(Chieh, Huo)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 前列腺癌增殖與轉移分子機轉及天然物治療之研究
(MOLECULAR MECHANISMS OF THE PROLIFERATION AND METASTASIS OF PROSTATE CANCER AND NATURAL COMPOUNDS THERAPIES)
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摘要(中) 中文摘要
前列腺癌是男性發生率第二高的癌症，並為世界第五最常見的癌症。前列腺癌病患接受雄激素治療以及去勢後腫瘤萎縮，但平均在1-3年內前列腺癌將會復發，希望能找尋潛在治療目標和晚期前列腺癌有效治療方法。
章3-1：我們發現了兩個天然化合物，蜂膠萃取物（CAPE）以及膽甾-3，5，6三醇，這兩種天然化合物顯示出對於前列腺癌細胞抗腫瘤活性具有療效。前列腺癌細胞LNCaP、104-R1、DU-145、22RV1、C4-2經由CAPE的誘導G1或G2 / M期的細胞週期停滯抑制細胞存活和去勢抗性前列腺癌（CRPC）細胞增殖的影響。CAPE經由調控Skp2的，P53，P21CIP1，和p27kip1而誘導細胞週期阻滯和生長抑制CRPC細胞。
章3-2：膽-3，5，6三醇經腹腔注射動物實驗後能有效抑制DU-145異種移植腫瘤體積減少了36％，膽甾-3，5，6三醇引發的前列腺癌細胞凋亡，G1細胞週期停滯。根據我們的研究結果，膽甾3，5，6三醇和CAPE將是晚期前列腺癌的有潛力的天然藥物。
章3-3：雄激素受體（AR）在前列腺癌的發生中有者不可或缺的作用。然而AR對前列腺癌轉移的作用尚不完全清楚。我們觀察到當AR過度表現在未具有AR的前列腺癌細胞之中，將抑制癌細胞運動及轉移。根據我們的研究結果，過度表現AR的PC-3細胞通過調控EMT標誌物蛋白和MMP活性可抑制細胞轉移和侵襲。
章3-4：藉由病人臨床樣品基因表現，發現相較於正常前列腺組織AKT3的mRNA表現量比早期未轉移前列腺腫瘤更低。AKT3蛋白表達在階段I，II，III的前列腺腫瘤較高於正常組織。 AKT3過度表達促進的列腺癌細胞的增殖，LNCaP、PC-3、DU-145和CA-HPV-10細胞。根據我們的研究結果AKT3的表達提供前列腺癌細胞生長優勢，然而AKT3可用於前列腺癌治療的潛在治療靶標指標。
我們發現PI3 / AKT激酶信號傳導途徑和雄激素受體（AR）在前列腺癌細胞的增殖和轉移的調控中發揮重要作用。 AKT3促進增殖抑制毛刺前列腺癌細胞的遷移和侵襲。 AR似乎是前列腺癌轉移腫瘤抑制。我們還確定了天然化合物CAPE和膽-3，5，6三醇成為去勢抵抗前列腺癌（CRPC）細胞的潛在治療藥物。根據我們的研究結果揭示了潛在治療目標和治療晚期前列腺癌潛力藥物。
摘要(英)

Prostate cancer is the second most frequently diagnosed cancer of men and the fifth most common cancer overall in the world. This disease is one of the most common non-cutaneous carcinoma of men in Western countries. Prostate cancer patients receiving androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer within 1-3 years.
Chapter 3-1: We discovered two natural compounds, caffeic acid phenethyl ester (CAPE) and cholestane-3, 5, 6-triol, exhibiting anti-cancer activity against prostate cancer cells. Treatment with CAPE suppressed cell survival and proliferation of castration-resistant prostate cancer (CRPC) cell via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4-2 CRPC cells. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21Cip1, and p27Kip1.
Chapter 3-2: Cholestane-3, 5, 6-triol is one of the most abundant and active oxysterol. Intraperitoneal injection of 1 mg of cholestane-3, 5, 6-triol daily for 14 days caused a 36% reduction in average volume of DU-145 xenograft. Cholestane-3, 5, 6-triol selectively suppressed proliferation of prostate cancer cells compared to normal prostate epithelial cells with IC50 ranging from 12-31 M. Cholestane-3, 5, 6-triol caused apoptosis, G1 cell cycle arrest, loss of -actin, and redistribution of -tubulin in prostate cancer cells. Our observations suggested that cholestane-3, 5, 6-triol and CAPE are potential chemotherapy agents for advanced prostate cancer.
Chapter 3-3: Androgen receptor (AR) plays essential role during development and progression of prostate cancer. However, the role of AR on prostate cancer metastasis is not fully understood. We observed that re-expression of AR, which locates in cytoplasmic in the absence of androgen, suppressed cell motility, migration, and invasion of PC-3 cells as determined by wound healing assay and transwell assay. Migration and invasion of PC-3 and PC-3AR cells was promoted by EGF or IGF-1 but was suppressed by Casodex. Re-expression of AR reduced activity of MMP-2 and MMP-9 in PC-3 cells. Our observations suggested that re-expressing AR suppresses migration and invasion of PC-3 cells via regulation of EMT marker proteins and MMP activity.
Chapter 3-4: Online database of clinical samples, including PubMed GEO profile or Oncomine, indicated that Akt3 mRNA expression level was higher in primary prostate tumors as compared to the normal prostate tissues. Immunohistochemical staining of 65 clinical samples revealed that Akt3 protein expression was higher in prostate tumors of stage I, II, III as compared to nearby normal tissues. Plasmid overexpression of Akt3 promoted cell proliferation of LNCaP, PC-3, DU-145, and CA-HPV-10 human prostate cancer cells, while knockdown of Akt3 by siRNA reduced cell proliferation in these cancer cells. Our observations implied that expression of Akt3 provides growth advantage for prostate cancer cells and Akt3 may be a potential therapeutic target for prostate cancer treatment.
We discovered that PI3/AKT kinase signaling pathway and androgen receptors (AR) play essential roles in regulation of proliferation and metastasis of prostate cancer cells. AKT3 promotes proliferation bur suppresses migration and invasion of prostate cancer cells. AR seems to be a tumor suppressor on prostate cancer metastasis. We also identified natural compounds CAPE and cholestane-3beta, 5alpha, 6beta-triol to be potential therapeutic agents for castration-resistant prostate cancer (CRPC) cells. In conclusion, our studies revealed potential therapeutic targets and treatments for advanced PCa
關鍵字(中) ★ 前列腺癌
★ 轉移分子機轉
★ 天然物治療		 關鍵字(英) ★ PROSTATE CANCER
★ METASTASIS
★ NATURAL COMPOUNDS
論文目次

TABLE OF CONTENTS
TABLE OF CONTENTS I
LIST OF FIGURES AND TABLES VI
ABBREVIATIONS IX
ABSTRACT XI
中文摘要 XII
CHAPTER 1
1. INTRODUCTION 1
 Prostate and Prostate cancer 1
 Roles of androgen receptor on Prostate cancer 1
 Prostate cancer cell model 2
 PI3K-Akt signaling pathway 2
 Caffeic Acid Phenethyl Ester 3
 Cholestane-3, 5, 6-triol 4
 Micro-Western Array 4
2. MATERIALS & METHODS 6
 Materials & Chemicals 6
 Cell Culture 6
 Cell Proliferation Assay 6
 Apoptosis Assays 7
 Flow Cytometry Cell Cycle Analysis 7
 Establishment of human Tumor Xenografts in Athymic Mice 8
 Transfection Overexpression and siRNA knockdown 8
 SDS-PAGE and Western Blotting Analysis 9
 Western Blotting Antibodies 9
 Micro-Western Array Blotting and Protein Level Quantification 10
 Quantitative Real-Time PCR (qRT-PCR) 10
 Quantitative Real-Time Polymerase Chain Reaction Primer 11
 Trans-well Cell Migration Assay and Invasion Assay 11
 Confocal Microscopy 12
 Wound Healing Assay 12
 Gelatin Zymography Assay 12
 Patients and Specimens 13
 Immunohistochemical analysis 13
 Online dataset Analysis 13
 Gene Correlation On-line Data Analysis 13
 Data Analysis 14
3. RESULT AND DISCUSSION 15
 3-1 Caffeic Acid Phenethyl Ester Induced Cell Cycle Arrest and Growth Inhibition in Androgen-Independent Prostate Cancer Cells via Regulation of Skp2, p53, p21 and p27 15
 CAPE treatment suppressed the proliferation and survival of castration-resistant prostate cancer (CRPC) cell lines 15
 CAPE treatment induced G1 or G2 cell cycle arrest in CRPC cells 15
 CAPE treatment retarded the growth of LNCaP 104-R1 xenograft in nude mice 16
 CAPE treatment affected the expression of proteins regulating cell survival, cell proliferation, cell cycle regulation, DNA damage checkpoint, and PI3K-Akt signaling pathway 16
 Conventional Western blotting assay was then used to confirm the changes of protein expression 16
 Skp2, p21Cip1, p27Kip1, and p53 are proteins important in regulating cell proliferation and cell cycle progression, while Chk1, Chk2, ATM, and ATR are DNA damage checkpoint proteins 16
 Overexpression of Skp2 rescued the suppressive effect of CAPE on cell proliferation of 104-R1 cells 17
 Knockdown of p27Kip1, p21Cip1, or p53 rescued the suppressive effect of CAPE on cell proliferation of LNCaP 104-R1 cells 17
 Co-treatment of CAPE with LY294002 or ABT737 suppressed proliferation of LNCaP 104-R1 cells 17
 3-2 Cholestane-3, 5, 6-triol Causes Apoptosis and Growth Inhibition in Human Prostate Cancer Cell Lines 24
 Cholestane-3, 5, 6-triol treatment retarded growth of androgen-insensitive DU-145 xenografts in nude mice 24
 Cholestane-3, 5, 6-triol suppressed proliferation of prostate cancer cells but not normal prostate epithelial cells 24
 Suppressive effect of cholestane-3, 5, 6-triol accumulated over time 24
 Cholestane-3, 5, 6-triol caused apoptosis in LNCaP prostate cancer sublines 24
 Cholestane-3, 5, 6-triol caused dysregulation of cell cycle 25
 Micro-Western Array analysis of protein expression affected by cholestane-3, 5, 6-triol treatment 25
 Cholestane-3, 5, 6-triol caused a reduction in abundance and activity of cell cycle promoting proteins and AKT signaling pathway proteins. 25
 Cholestane-3, 5, 6-triol treatment disturbed actin and tubulin in prostate cancer cells 25
 Co-treatment of cholestane-3, 5, 6-triol and hormone therapy caused additive suppression in prostate cancer cells 26
 Structure-related oxysterols suppress proliferation of castration-resistant prostate cancer cells 26
 3-3 Androgen Receptor Inhibits Epithelial-Mesenchymal Transition, Migration, and Invasion of PC-3 Prostate Cancer Cells 31
 Re-expression of AR protein suppressed migration and invasion of PC-3 cells 31
 Re-expression of AR affected signaling and EMT marker proteins 31
 EGF, IGF-1, and anti-androgen affect migration and invasion of PC-3 and PC-3AR cells 31
 Activity of MMP-2 and MMP-9 is lower in PC-3AR cells as compared to PC-3 cells 32
 3-4 Elevation of Akt3 Promotes Proliferation of Prostate Cancer Cells via regulation of Akt phosphorylation, B-Raf, TSC1, and TSC2 35
 Expression of Akt3 mRNA and protein level elevates in primary prostate tumors 35
 Elevation of Akt3 protein level promotes proliferation of prostate cancer cells 35
 Elevation of Akt3 protein increases protein abundance of B-Raf and phosphorylation of Akt while decreases expression of TSC1 and TSC2 proteins 35
 Correlation between AKT3, BRAF, TSC1, and TSC2 genes in prostate cancer tissues 36
 Inhibition of B-Raf suppresses proliferation while knockdown of TSC1 induces proliferation of prostate cancer cells 36
CONLUSION 39
FIGURES AND TABLES 40
REFERENCES 83
參考文獻



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指導教授 高永旭(Yung-Hsu Kao) 審核日期 2016-5-27
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