Combination of prodrugs perforin-CEBPD and perforin-granzyme B enhance a stronger activation of caspase signaling in efficiently killing prostate cancer

• Main Authors: Yun-HsuanChou, 周昀璇
• Other Authors: Ju-Ming Wang
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/97970177654310981421

碩士 === 國立成功大學 === 藥理學研究所 === 100 === Prostate cancer is the most common malignancy in men and the third leading cause of male cancer-related deaths in the Western world. In Taiwan, the incidence of prostate cancer has been rapidly increasing in the past 10 years. The standard therapies include androgen ablation that initially causes tumor regression. However, tumor cells will eventually relapse and develop into castration-resistant prostate cancer (CRPC). Overexpression of transcription factor CCAAT/enhancer binding protein delta (CEBPD) takes part in inducing growth arrest and apoptosis in cancer cells, which could serve as a potential tumor suppressor. Notably, in this study we demonstrated CEBPD is an androgen responsive gene, suggesting CEBPD may play a functional role in progression and development of prostate cancer. Moreover, we found that the activation of E2F1/EZH2/SUZ12 axis participates in CEBPD silencing in CRPC. We next identified that Caspase 8 gene, an apoptosis activator, is a CEBPD downstream target. Reporter assay and in vivo DNA binding assay revealed that CEBPD directly binds and activates Caspase 8 promoter activity. To achieve the idea of “reactivation of CEBPD” for the therapy of prostate cancer and to avoid the epigenetic effects on CEBPD promoter in CRPC, we therefore applied a protease-specific perforin-fused prodrug system for this issue. Our results suggest that the combination of CEBPD prodrug (induction of procaspase 8 level) and granzyme B prodrug (an activator of procaspase 8) could trigger stronger apoptotic effect and impede their proliferation in androgen dependent prostate cancer and CRPC. Accordingly, protease-specific perforin-fused prodrug therapy offers a new therapeutic strategy in treating prostate cancers.