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研究生:鍾麗娟
研究生(外文):Li-chuan Chung
論文名稱:探討低氧及低氧模擬物對前列腺癌細胞之影響
論文名稱(外文):UNDERSTANDING THE EFFECTS OF HYPOXIA AND HYPOXIA-MIMETIC AGENTS IN THE HUMAN PROSTATE CARCINOMA CELLS
指導教授:李綉鈴
指導教授(外文):Shiow-Ling Lee
學位類別:博士
校院名稱:大同大學
系所名稱:生物工程學系(所)
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2011
畢業學年度:100
語文別:英文
論文頁數:126
中文關鍵詞:細胞週期低氧模擬物低氧薑黃素前列腺癌前列腺特異性抗原
外文關鍵詞:hypoxiaHIF-1amimosinePSAdimethyloxalylglycineNDRG1BTG2androgen receptorcurcumin
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L-mimosine及Dimethyloxalylglycine (DMOG)皆是酺胺酸羥基酶抑制劑 (prolyl hydroxylase inhibitors),可抑制癌細胞生長。L-mimosine 及DMOG亦能穩定低氧誘導因子(HIF-1α)蛋白質,具有類似低氧的效果,常被用於體外及體內的低氧模擬實驗。B-cell translocation gene 2(BTG2)主要調控細胞週期中G1/S期。N-myc downstream-regulated gene 1 (NDRG1) 為一抑癌的基因,會促進細胞分化而抑制癌細胞生長、腫瘤形成及轉移。前列腺特異抗原(Prostate-specific antigen, PSA)是由前列腺上皮管腔細胞所分泌,而血清PSA 濃度是評估及診斷前列腺癌症的重要標誌。此博士論文主要探討低氧及低氧模擬物質對前列腺癌細胞之影響。以3H-thymidine incorporation及流式細胞儀分析發現L-mimosine 可促使PC-3 及 LNCaP 細胞週期分別停留於 G1 或 S 期,進而抑制細胞生長。從西方點墨法及短暫性基因報導分析法發現L-mimosine及低氧可穩定 PC-3 及 LNCaP 細胞的HIF-1α,進而誘導BTG2及NDRG1的蛋白質表現,但是降低週期素A (cyclin A) 的蛋白質表現。在LNCaP 細胞剔減 (knockdown) HIF-1α基因後,低氧或L-mimosine所誘導BTG2 及 NDRG1蛋白質表現增加的情形便減緩。該結果顯示L-mimosine 抑制前列腺癌細胞 PC-3 及 LNCaP 的生長是經由調控 BTG2 及 NDRG1 基因的轉錄,且此調控機轉需依賴細胞內HIF-1α的存在。西方點墨法及酵素連結免疫分析法(ELISA)結果亦發現,L-mimosine 及 DMOG穩定 HIF-1α蛋白質並誘導 PSA 的基因表達於LNCaP細胞。經由短暫性基因報導分析法也顯示低氧促使PSA基因表達需依賴細胞內 HIF-1α及雄性素受體(AR)的表現。薑黃素(curcumin) 可以降低因低氧所促進的AR蛋白質表現,但卻不影響HIF-1α 及血管內皮生長因子(VEGF) 蛋白質表現。ELISA及短暫性基因報導分析法也顯示薑黃素可阻斷L-mimosine 或 DMOG 對PSA基因的活化。綜合上述,此博士論文的研究結果顯示低氧及低氧模擬物質(L-mimosine及Dimethyloxalylglycine)可經由穩定HIF-1α蛋白質而促進 BTG2及NDRG1基因的表現,並抑制前列腺癌細胞 PC-3 及 LNCaP 的增生。同時,L-mimosine 及 DMOG與低氧處理亦可誘導PSA基因的表達。而藉由curcumin處理可經由抑制AR蛋白質的表現進而阻斷低氧及低氧模擬物質對PSA基因的活化。
L-mimosine and dimethyloxalylglycine (DMOG) are prolyl 4-hydroxylase inhibitors stabilizing the hypoxia-inducible factor-1α (HIF-1α) and are used to mimic the effects of hypoxia in vivo and in vitro. The B-cell translocation gene 2 (BTG2) regulates the G1/S transition phases of the cell cycle. N-myc downstream-regulated gene 1 (NDRG1) is a differentiation-inducing gene upregulated by hypoxia. Prostate-specific antigen (PSA) is a well-known biomarker for diagnosing and evaluating the status of prostate cancer. Studies of this dissertation are to evaluate the effects of hypoxia and hypoxia mimetics on prostate carcinoma cells. The 3H-thymidine incorporation and flow cytometry assays revealed that the L-mimosine arrested the cell cycle at the G1 phase in PC-3 cells and at S phase in LNCaP cells, thus attenuating cell proliferation. Immunoblot assays indicated that hypoxia and L-mimosine stabilized HIF-1α and induced BTG2 and NDRG1 protein expression, but downregulated protein levels of cyclin A in both PC-3 and LNCaP cells. The transient gene expression assay revealed that L-mimosine treatment or co-transfection with HIF-1α expression vector enhanced the promoter activities of BTG2 and NDRG1 genes. Knockdown of HIF-1α attenuated the increasing protein levels of both BTG2 and NDRG1 by hypoxia or L-mimosine in LNCaP cells. Immunoblot and enzyme-linked immunosorbent (ELISA) assays indicated that L-mimosine and DMOG stabilized HIF-1α and induced PSA gene expression in LNCaP cells. Further studies indicated that induction of the PSA expression by hypoxia is both HIF-1α- and AR-dependent. Immunoblot assays revealed that a curcumin treatment decreased the protein level of AR but did not significantly affect the protein levels of HIF-1α and vascular endothelial growth factor (VEGF) which were induced by hypoxia. ELISA and transient gene expression assays indicated that curcumin blocked the activation of L-mimosine or DMOG treatment on PSA expression. In conclusion, results of this dissertation indicated that hypoxia and L-mimosine modulated BTG2 and NDRG1 at the transcriptional level, which is dependent on HIF-1α. L-mimosine enhanced expression of BTG2 and NDRG1, which attenuated cell proliferation of the PC-3 and LNCaP prostate carcinoma cells. L-mimosine and DMOG stabilized HIF-1α and induced PSA gene expression. The curcumin blocked the AR protein expression, which attenuated the enhanced effect of PSA expression by L-mimosine and DMOG that induce hypoxia condition.
TABLE OF CONTENTS
ACKNOWLEDGMENTS i
ABSTRACT.iii
CHINESE ABSTRACT.v
TABLE of CONTENTS vii
LIST OF TABLES x
LIST OF FIGURES xi
ABBREVIATION LIST xiii
CHAPTER 1 INTRODUCTION 1
1.1. Overview 1
1.2. Literature Review 3
1.2.1. Hypoxia inducible factor-1 (HIF-1) 3
1.2.2. B-cell translocation gene 2 (BTG2) 6
1.2.3. N-myc downstream-regulated gene 1 (NDRG1) 7
1.2.4. Prostate specific antigen (PSA) 8
1.2.5. L-mimosine.10
1.2.6. Dimethyloxalylglycine (DMOG) 11
1.2.7. Curcumin 12
1.3. Purposes of the Research 13
CHAPTER 2 MATERIALS AND METHODS 16
2.1. Cell Culture and Chemicals 16
2.2. Cell Proliferation Assay with 3H-Thymidine Incorporation 17
2.3. Flow Cytometry 18
2.4. Immunoblotting Assay 19
2.5. Real-Time Reverse Transcription-Polymerase Chain Reaction 20
2.6. Expression Vector 21
2.6.1. Human HIF-1α expression vector 21
2.6.2. Human androgen receptor (AR) expression 21
2.7. Knockdown HIF-1α 22
2.8. Reporter Vectors 23
2.9. BTG2 reporter vectors 23
2.10. NDRG1 reporter vectors 24
2.11. PSA reporter vectors 25
2.12. Transient Transfection and Reporter Assay 26
2.13. Prostate-Specific Antigen Enzyme-Linked Immunosorbent Assay 27
2.14. Statistical Analysis27
CHAPTER 3 RESULTS 29
3.1. L-mimosine Blocks Cell Proliferation via Upregulation of B-cell Translocation Gene 2 and N-myc Downstream Regulated Gene 1 in Prostate Carcinoma Cells 29
3.1.1. L-mimosine inhibited cells growth and cell proliferation in PC-3 cells 29
3.1.2. L-mimosine inhibited cells growth and cell proliferation in LNCaP cells 32
3.1.3. Effect of hypoxia on gene expression of LNCaP and PC-3 cells 34
3.1.4. Hypoxia and L-mimosine upregulate gene expression of BTG2 37
3.1.5. L-mimosine upregulates gene expression of NDRG1 of prostate carcinoma cells 40
3.1.6. Hypoxia upregulates gene expression of NDRG1 of prostate carcinoma cells 42
3.1.7. Hypoxia and L-mimosine upregulate gene expression of BTG2 and NDRG1 is dependent on HIF-1α 44
3.2. Curcumin Provides Potential Protection Against the Activation of Hypoxia and Prolyl 4-hydroxylase Inhibitors on Prostate-Specific Antigen Eexpression In Human Prostate Carcinoma Cells 46
3.2.1. Effect of hypoxia on gene expression of PSA in LNCaP cells 46
3.2.2. Effect of L-mimosine on prostate cancer cell growth and PSA gene expression 48
3.2.3. Effect of DMOG on prostate cancer cell growth and PSA gene expression 50
3.2.4. Upregulation of L-mimosine on the gene expression of PSA is due to iron chelation 52
3.2.5. Effect of hypoxia on PSA expression depends on the synergy of HIF-1α and AR on the enhancer region of the PSA gene 54
3.2.6. Curcumin blocks the increases of hypoxia and prolyl 4-hydroxylase inhibitors on PSA expression 57
CHAPTER 4 DISCUSSION 61
CHAPTER 5 CONCLUSIONS 73
CHAPTER 6 REFERENCES 78
APPENDIX 98
LIST OF TABLES
Supplementary table 1: Characterization of LNCaP, PC-3 and PCJ prostate cancer cell lines 98
Supplementary table 2: The summary of primary and secondary antibody in immunoblotting assay 99
LIST OF FIGURES
Figure 1 Effect of L-mimosine on cell cycle distribution and cell proliferation in PC-3 cells 31
Figure 2 Effect of L-mimosine on cell cycle distribution and cell proliferation in LNCaP cells 33
Figure 3 Hypoxia modulates gene expression of LNCaP and PC-3 cells 36
Figure 4 Hypoxia and L-mimosine modulate the gene expression of BTG2 in prostate carcinoma cells 38
Figure 5 L-mimosine modulates the gene expression of NDRG1 of prostate carcinoma cells 41
Figure 6 Hypoxia modulates the gene expression of NDRG1 of prostate carcinoma cells 43
Figure 7 HIF-1α knockdown attenuates the activation of hypoxia and L-mimosine on gene expression of NDRG1 and BTG2 of LNCaP cells 45
Figure 8 Hypoxia modulates PSA gene expression of LNCaP cells 47
Figure 9 L-mimosine modulates the cell proliferation and gene expression of PSA in LNCaP cells 49
Figure 10 Dimethyloxalylglycine modulates the cell proliferation and gene expression of PSA in LNCaP cell 51
Figure 11 The L-mimosine-enhanced gene expression of PSA is due to iron chelation 53
Figure 12 The synergy of HIF-1α and AR by hypoxia is dependent on the enhancer region of the 5′-flanking of the PSA gene 56
Figure 13 Curcumin blocks the increasing of hypoxia and prolyl 4-hydroxylase inhibitors on PSA expression 59
Figure 14 The modulated mechanisms of hypoxia and hypoxia- mimetic agents on the gene expression of BTG2, NDRG1, PSA and the mechanisms for blocking the activation of hypoxia-mimetic agents on PSA expression using curcumin in the human prostate carcinoma cells 77
Supplementary figure 1: The chemical structure of L-mimosine (Sigma) 100
Supplementary figure 2: The chemical structure of DMOG (Sigma) 101
Supplementary figure 3: The chemical structure of FAC (Sigma) 102
Supplementary figure 4: The chemical structure of chetomin (Sigma) 103
Supplementary figure 5: The chemical structure of curcumin (Sigma) 104
Supplementary figure 6: The construction map of HIF-1? expression vector 105
Supplementary figure 7: The construction map of AR expression vector 106
Supplementary figure 8: The construction map of BTG2 reporter vector 107
Supplementary figure 9: The construction map of NDRG1 reporter vector 108
Supplementary figure 10: The construction map of PSA promoter / enhancer reporter vector 109
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