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This dissertation, Effect of FTY720 on the Growth and Invasion Ability of Androgenindependent Prostate Cancer Cells by Chun, Zhou, 周純, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Effect of FTY720 on the Growth and Invasion Ability of Androgen- independent Prostate Cancer Cells Submitted by ZHOU Chun for the degree of Master of Philosophy at the University of Hong Kong in August 2005 Prostate cancer is one of most frequently diagnosed cancers in the Western world. The incidence of prostate cancer in Asia, including Hong Kong is also increasing in the past ten years. The failure to control androgen-independent and metastatic prostate cancer growth is the main cause of death in prostate cancer patients. In this study, we have investigated the effect of a novel anticancer agent, FTY720, a fungus metabolite, in the suppression of survival and metastatic abilities of androgen-independent prostate cancer cells. The first part of this study was to study the effect of FTY720 on the growth and survival of two androgen-independent prostate cancer cell lines, DU145 and PC3. Firstly, using colony forming assay, we found that FTY720 treatment led to decreased colony forming ability of these cancer cells, indicating its negative role on cancer cell survival. In addition, treatment with relatively low dose of FTY720 (i.e. Inhibitory Concentration of 50 or 90% cell survival) resulted in suppression of proliferation of prostate cancer cells as demonstrated by proliferation assay. MTT (3-[4,5-dimethylthiazol-2-yl]-2.5-diphenyl tetrazolium bromide) assay further confirmed that FTY720 could efficiently inhibit the viability of DU145 and PC3 cells. However, at higher doses, FTY720 was able to induce iapoptosis in DU145 and PC3 cells as evidenced by DAPI staining and DNA ladder assay. We also found that the FTY720-induced apoptosis was associated with down-regulation of Bcl-2 and activation of caspase-3. The second part of this study was focused on the inhibitory effect of FTY720 on the invasive and metastatic abilities of DU145 and PC3 cells. At the dose of IC50, cell migration ability was suppressed by FTY720 as demonstrated by Wound closure assay. Using 3-D collagen gel invasion assay and stress fiber staining, we found that FTY720 was also able to inhibit the invasive and metastatic abilities of these two cancer cell lines. Furthermore, we found that the inhibitory effect of FTY720 on the metastatic abilities of prostate cancer cells was associated with down-regulation of GTP-bound active form of RhoA. Transfection of a dominant-active RhoA vector in DU145 and PC3 cells conferred resistance to FTY720. These results indicate that FTY720 may inhibit metastatic ability of androgen-independent prostate cancer cell lines through inactivation of RhoA-GTPase pathway. In conclusion, at relatively low doses, FTY720 was able to inhibit metastatic abilities and survival of androgen-independent prostate cancer cells. At relatively high doses, FTY720 effectively induced apoptosis of androgen-independent prostate cancer cells. These results implicate a potential role of FTY720 as a therapeutic agent against androgen-independent prostate cancer. (413 words) ii DOI: 10.5353/th_b3168574 Subjects: Antineoplastic agentsProstate - Cancer - ChemotherapyCancer cells

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