臺灣博碩士論文加值系統

前列腺癌是美國男性最常見的癌症，也是繼肺癌之後造成癌症死亡的第二位主因。前列腺癌在台灣的發生率也是逐年不斷地增加，已成為成男性癌症死亡的第七位。侵犯與轉移仍然是決定治療前列腺癌患者成功與否的最大阻礙。化學治療在生殖泌尿腫瘤之應用，一般為腫瘤出現無法手術、復發或轉移時。而當賀爾蒙治療無效時，前列腺癌往往變成具有抗藥性。因此，研究因賀爾蒙治療無效引發其產生抗藥性的分子機轉，進一步從中找到新的有效替代療法，改善目前前列腺癌的治療。
我們實驗室發展出基因矩陣(cDNA microarray)的技術來篩選參與前列腺癌抗藥性形成的可能基因，並藉此找到有效的臨床治療新標的基因。在比對大鼠前列腺癌抗藥性子細胞株(AT3/ADR1000)與母細胞株的實驗中發現，有數種基因高度表達在抗藥性子細胞株中，我們將焦點放在巨嗜細胞驅化抑制因子(macrophage migration inhibitory factor; MIF)，榖胱甘硫轉移酶(glutathione S-transferase pi; GSTpi)，抑制分化因子(Inhibition of Differentiation-1; Id-1)等基因，因為根據文獻報導此三個基因與腫瘤發生和轉移有相關性。
首先，為了要確定這些基因與前列腺後天抗藥性產生的相關性，我們利用基因的轉染建立了分別大量表達Id-1，MIF和GSTpi的細胞株，並測試這些轉染細胞株對於不同的化療藥物如doxorubicin，paclitaxel和cyclophosphamide的細胞毒性的變化。細胞毒性試驗結果顯示，大量表達Id-1的細胞株增加對doxorubicin，paclitaxel和cyclophosphamide化療藥物的抗藥性， MIF的表現可驅使細胞增加對paclitaxel的抗藥性，GSTpi的表達可提供對doxorubicin和cyclophosphamide的抗藥性。此外，MIF和GSTpi的表達會引發多重抗藥基因multi-drug resistant gene-1 (mdr-1)的表達。
為了進一步研究前列腺癌細胞多重抗藥性細胞株MIF以及GSTpi與mdr-1基因表達的相關性，我們利用經過基因轉染的細胞株來探討mdr-1基因表達是否會因MIF或GSTpi的表達而改變，而因MIF或GSTpi表達所造成醣化蛋白-170的過度產生是否為可提供泌尿道癌細胞抗藥性的機轉。結果顯示，前列腺癌細胞多重抗藥性細胞株中的醣化蛋白-170產量與MIF及GSTpi蛋白質量都明顯增加。而不管在MIF或GSTpi 的永久性轉染細胞株中，其多重抗藥基因的表達與醣化蛋白-170的產生都明顯高於控制組。進一步利用HEK細胞株暫時性轉染MIF或GSTpi基因觀察醣化蛋白-170的變化，細胞流式分析結果顯示醣化蛋白-170的表達隨著基因轉染的劑量增加而增加。而細胞敏感性試驗顯示隨著醣化蛋白-170的增加細胞的存活率亦隨之增加。
為了探討Id-1在前列腺癌提供抗藥性機轉的研究，我們利Id-1的永久性轉染的細胞株研究Id-1表達及下游訊息傳遞對前列腺癌多重抗藥性產生的影響。我們發現Id-1的過度產生可驅使AT3細胞對doxorubicin，paclitaxel 和cyclophosphamide產生抗藥性，但此抗藥性並非引發多重抗藥性基因的表達。在doxorubicin 的處理下，細胞會因Id-1的表達而抑制p38MAPK 和c-jun N-terminal kinase (JNK) 訊息的傳遞。以p38MAPK and JNK 抑制劑處理Id-1的永久性轉染的細胞株會降低doxorubicin引發的細胞凋亡. 相對的， 以extracellular signal-regulated kinase (ERK) 抑制劑處理Id-1的永久性轉染的細胞株會使得細胞對藥物引發的凋亡更為敏感。總結，Id-1的過度表達是藉由抑制p38MAPK and JNK 訊息傳遞而影響前列腺癌的抗藥性。此外，持續的活化ERK可提供細胞的對抗藥物引發的細胞毒性。
總結，我們的數據提供了幾個重要的訊息: 1)利用多重抗藥細胞模式結合cDNA microarray方法，我們成功的篩選到三個大量表現在多重抗藥細胞株的重要基因，而此基因的過度表達提供前列腺癌的抗藥性；2)雖然過度表達MIF 和GSTpi基因會引發多重抗藥基因的表達，但它們無法提供所有的前列腺癌多重抗藥細胞的抗藥表現型態的特性，那意味著有其他的機轉提供前列腺癌的抗藥特性；3) Id-1， MIF和 GSTpi可能不只因引發多重抗藥基因的表達並且藉由其個別的生物功能；4) 細胞過度表達Id-1可使ERK 持續的活化，且伴隨JNK和p38MAPK的抑制，導致細胞對藥物引發的凋亡更具有抗藥性。無論如何，這些基因的交互作用與前列腺癌抗藥性的獲得將在未來的動物實驗中做進一步的研究。

Prostate carcinoma is the most common malignancy in males and is the second leading cause of cancer mortality in the United States after lung cancer. Now prostate cancer occurrence increased recently in Taiwan and became the seventh leading cause of cancer mortality. Invasion and metastasis is still the greatest obstacles to the successful treatment of patients with prostate cancer. Chemotherapy is the choice of therapy for genital urinary tract cancer, when they were unresectable, recurrent or metastasis. But prostate cancer always possesses drug-resistance in this situation after hormonal therapy is of no use. Therefore, the molecular mechanisms of drug-resistance derived from hormone refractory should be investigated to find out a new target of effective alternative therapy for the treatment of prostate cancer.
Our laboratory has developed cDNA microarrays to screen the potential genes that involve the development of drug resistance of prostate cancer and try to find a new efficient therapy target for clinic treatment. There are several genes up-regulated in multidrug resistance cell line of rat prostate cancer when compared with native cells. We narrowed to three highly potential genes including macrophage migration inhibitory factor (MIF), glutathione S-transferases (GSTs), and Inhibition of Differentiation-1 (Id-1) because they are reported to associated with tumorgenesis or metastasis.
At first, we identified the relationship between these genes and acquired drug resistance of prostate cancer, we established the prostate cancer transfectants that overexpressed Id-1, MIF and GSTpi, respectively, and tested the inhibitory effect of the cytotoxicity to different chemotherpeutic agents such as doxorubicin, paclitaxel and cyclophosphamide. The cytotoxity assay results demonstrated that cells overexpressing the Id-1 gene can increase in their resistance to doxorubicin, paclitaxel and cyclophosphamide. MIF expression can drive cells increase in their resistance to paclitaxel, and GSTpi expression confers drug resistance to doxorubicin and cyclophosphamide. In addition, the induction of mdr1 gene expression was noted in upregulation of MIF and GSTpi.
To further investigate the relationship between MIF as well as GSTpi and the expression of mdr-1 gene in MDR subline of prostate cancer cells, we used these stable transfectants to determine whether the expression of mdr-1 should be modulated by MIF or GSTpi expression and whether the overproduction of p-glycoprotein driving by MIF or GSTpi confers the resistance to prostate cancer cells. The results showed that the production of gp-170 increased in MDR sublines of prostate cancer accompanying the upregulation of MIF and GSTpi in protein level. The expression of mdr-1 gene and the production of pg-170 increased in either MIF or GSTpi stable transfectants when compared with vector control. The human embryonic kidney (HEK) cells transiently transfected with the eukarytonic expression vector driving MIF or GSTpi protein presented the increased production of gp-170 protein using flow cytometric analysis. The MTT results demonstrated that the reduced chemocytotoxicity was correlated with the increased production of gp-170 protein in MIF and GSTpi transfectants.
To determine the molecular mechanism of Id-1 conferring the drug resistance in prostate cancer, we used the Id-1 stable transfectants to investigate and determine the effect of Id-1 expression and its underlying pathways on the development of multidrug resistance of prostate cancer. We found that Id-1 overproduction drove AT3 cells to become resistant to chemotherapeutic agents such as doxorubicin, taxol and cyclophosphamide but not due to the expression of mdr-1. The p38MAPK and c-jun N-terminal kinase (JNK) pathways were suppressed, and this correlated with increased expression of Id-1 after doxorubicin challenge. Treatment of the Id-1 expressing cells with p38MAPK and JNK inhibitors resulted in decreased doxorubicin-induced apoptosis. In contrast, Id-1 expressing cells treated with extracellular signal-regulated kinase (ERK) inhibitor made cells more sensitive to drug-induced apoptosis. In conclusion, overexpression of Id-1 can affect drug resistance of prostate cancer through the inhibition of p38MAPK and JNK pathways. In addition, sustained activation of ERK could provide cellular resistance to drug-induced cytotoxicity.
In conclusion, our data have provided following important informations: 1) using this MDR cells model combined with cDNA microarray method, we have successfully screened three important genes that overexpressed in MDR cell lines and its overexpression confer drug resistance in prostate cancer cells; 2) although overexpression of MIF and GSTpi genes induced mdr1 genes expression, they were unable to carry out all of the drug resistance phenotypic characteristics of MDR prostate cancer cells. It indicated there were alternative mechanisms that also confer drug resistance in prostate cancer; 3) Id-1, MIF and GSTpi may confer drug resistance not only due to the induction of mdr1 gene expression but also through their individual biological function. 4) overexpression of Id-1 in cells may lead to sustained activation of the ERK accompanying inhibition of the JNK and p38MAPK that results in promoting cells to be more resistant to drug-induced apoptosis. However, the cooperation of these three genes in the acquisition of drug resistant in prostate cancer cell line will be further addressed in animal models.

TABLE CONTENTS
TITLE…………………………………………………………………… I
ACKNOWLEDEMENTS……………………………………………… II
TABLE CONTENTS…………………………………………………… III
LIST OF FIGURES AND TABLES…………………………………… IIV
ENGLISH SUMMARY………………………………………………… IX
CHINESE SUMMARY………………………………………………… XIII
ABBREVIATIONS……………………………………………………… XVII

Chapter 1. General Introduction
1.1. Epidemiology of Prostate Cancer…………………………………… 1
1.1.1 Androgen receptor and androgen metabolism………………… 2
1.1.2. Insulin-like growth factors…………………………………… 4
1.1.3. Dietary factors………………………………………………… 5
1.2. Pathogenesis of Prostate Cancer
1.2.1. Early prostate cancer………………………………………… 7
1.2.2. Development of hormone-refractory tumors…………… 8
1.2.3. Progression, metastasis, and the role of tumor microenvironment 10
1.2.4. Bone Metastasis ……………………………………………… 13
1.3. Treatment of Prostate Cancer
1.3.1. Early-stage prostate cancer………………………………… 15
1.3.2. Metastatic prostate cancer…………………………………… 17
1.3.3. Hormone-refractory prostate cancer ……………………… 19
1.4. Further Study…………………………………………………… 21

Chapter 2. Association of Id-1, MIF and GSTpi with Multidrug Resistance in Prostate Cancer
2.1. Introduction………………………………………………………… 22
2.2. Material and Methods……………………………………………… 25
2.3. Results
2.3.1. Up-regulation of Id-1, MIF and GSTpi genes in multi-drug resistant cells of prostate cer …31
2.3.2. Establishment of stable cell lines overexpressing Id-1, MIF and GSTpi …31
2.3.3. Chemoresistance of cell lines………………………………… 32
2.3.4. Apoptotic activity analysis…………………………………… 33
2.3.5. Expression of mdr1 gene in transfectants…………………… 33
2.4 Discussion…………………………………………………………… 34

Chapter 3. Modulation of Multidrug Resistance MDR-1 Gene by MIF and GSTpi in Prostate Cancer Cells
3.1. Introduction………………………………………………………… 42
3.2. Material and Methods……………………………………………… 46
3.3. Results
3.3.1. Up-regulation of mdr-1 in multidrug resistance cell line cells 51
3.3.2. Production of MIF and GSTpi in multidrug resistance cell line of prostate cancer 51
3.3.3. Induction of p-gp170 expression by MIF and GSTpi expression… 52
3.3.4. Chemoresistance in MIF and GSTpi transfectant clones………53
2.4 Discussion …………………………………………………………… 54

Chapter 4. Downregulation of JNK and p38MAPK by Id-1 Decreases Chemosensitivity to Doxorubicin in Prostate Cancer Cells
4.1. Introduction ………………………………………………………… 59
4.2. Material and Methods ……………………………………………… 62
4.3. Results
4.3.1. Upregulation of Id-1 in multidrug-resistant prostate cancer cells 68
4.3.2. Drug resistance of Id-1 transfectant cells ……………………69
4.3.3. Regulation of JNK and p38MAPK cascades by Id-1 expression70
4.3.4. Effect of Id-1 expression on drug-induced cytotoxicity through the regulation of MAPK cascades …71
4.4 Discussion …………………………………………………………… 73

Chapter 5. Conclusion ………………………………………………… 78
References………………………………………………………………… 79
Figures……………………………………………………………………… 103
Tables……………………………………………………………………… 124
Appendices………………………………………………………………… 129

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