Choi, Mei Yuk. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 79-89). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.iii / Abstract (Chinese) --- p.v / List of Abbreviations --- p.vii / List of Figures --- p.viii / Chapter Chapter 1 --- Introduction / Chapter 1.1. --- General introduction of cancer --- p.1 / Chapter 1.2. --- Overview of apoptosis --- p.2 / Chapter 1.2.1. --- The extrinsic death receptor pathway --- p.4 / Chapter 1.2.2. --- The intrinsic mitochondrial pathway --- p.4 / Chapter 1.2.3. --- Cross-talk between the intrinsic and extrinsic pathways --- p.5 / Chapter 1.3. --- Overview of selenium --- p.6 / Chapter 1.3.1. --- Selenium and prostate cancer --- p.7 / Chapter i. --- Epidemiological studies --- p.7 / Chapter ii. --- Clinical trials --- p.8 / Chapter iii. --- Preclinical investigations --- p.10 / Chapter a. --- in vivo studies --- p.11 / Chapter b. --- in vitro studies --- p.12 / Chapter c. --- selenocystine and prostate cancer --- p.13 / Chapter 1.4. --- Objective --- p.15 / Chapter Chapter 2 --- Materials and methods / Chapter 2.1. --- Materials --- p.18 / Chapter 2.2. --- Methods --- p.19 / Chapter 2.2.1. --- Cell culture --- p.19 / Chapter 2.2.2. --- MTT assay --- p.19 / Chapter 2.2.3. --- Cell cycle distribution analysis --- p.20 / Chapter 2.2.4. --- TUNEL assay and DAPI staining --- p.20 / Chapter 2.2.5. --- Evaluation of mitochondrial membrane potential (ΔΨm) --- p.21 / Chapter 2.2.6. --- Measurement of superoxide generation (DHE assay) --- p.22 / Chapter 2.2.7. --- Inhibition of superoxide generation --- p.22 / Chapter 2.2.8. --- Western blot analysis --- p.23 / Chapter 2.2.9. --- Statistical analysis --- p.24 / Chapter Chapter 3 --- Results / Chapter 3.1. --- The antiproliferatvie effect of SeC on LNCaP and PC-3 cells --- p.25 / Chapter 3.2. --- The role of caspases in SeC-induced apoptosis --- p.34 / Chapter 3.3. --- The effect of SeC on the mitochondrial membrane potential --- p.39 / Chapter 3.4. --- The involvement of p53 in SeC-treated LNCaP cells --- p.44 / Chapter 3.5. --- MAPK and PI3K/Akt signaling pathways --- p.47 / Chapter 3.6. --- The role of superoxide in SeC-induced apoptosis --- p.52 / Chapter Chapter 4 --- Discussion --- p.62 / Chapter Chapter 5 --- Conclusion --- p.74 / References --- p.79

Prostate cancer remains one of the most commonly diagnosed cancers in men and is a leading cause of cancer death. While great success has been achieved at curing early stage prostate cancer, limited success has been obtained when treating late-stage hormone independent prostate cancer. This is due to the increased propensity for skeletal and non-skeletal metastases. Thus development of novel effective therapeutic modalities against late stage prostate cancer is of critical importance. / Towards these objectives, I have focused my attention on the role of prostate secretory protein (PSP-94) which is expressed in normal individuals and in patients with early stage prostate cancer. Using our well established in vivo models of prostate cancer, I have evaluated the ability of PSP-94 and its amino acids 31-45 required (PCK3145) to decrease tumor growth and skeletal metastases in vivo and evaluated the potential mechanism(s) associated with PCK3145 anti-cancer actions. / Prostatic cancer can also develop as a result of epigenetic activation of tumor promoting genes. To evaluate the role of methylation in prostate cancer, late stage prostate cancer cells were treated with the universal methylating agent S-adenosylmethionine (SAM) and an anti-sense oligonucleotide directed against MBD2 (AS). Scrambled oligonucleotide was included as a control (S). Both SAM and MBD2-AS resulted in inhibition in uPA, MMP-2 and VEGF production leading to decreased tumor cell invasive capacity. However, SAM and MBD2-AS were not able to either further repress partially methylated genes (GSTP1) or reactivate already methylated genes (AR). Furthermore, SAM and MBD2-AS treatment resulted in significant reduction in tumor growth in vivo . Immunohistochemical and RT-PCR analyses carried out on SAM and MBD2-AS tumors revealed decreased protein and mRNA expression of uPA and MMP-2 which was partially due to increased methylation of the respective promoters even after 10 weeks post in vitro treatment as analyzed by bisulfate sequencing. In addition decreased levels of angiogenesis and tumor survival markers were observed. / Collectively, these studies are aimed at the development of novel reliable approached to diagnose and treat advanced, hormone refractory prostate cancer to reduce tumor associated morbidity and mortality.

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