摘要
Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS
Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2–8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients. RESULTS
Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P ≪ 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P ≪ 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal. CONCLUSIONS
Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer. Prostate 50: 179–188, 2002. © 2002 Wiley-Liss, Inc.
摘要译文
前列腺癌对雄激素独立（AI）的结果如下雄激素戒断，和雄激素非依赖性疾病进展部分来自的抗凋亡基因的上调仍然是主要的障碍提高生存率。睾酮抑制前列腺消息-2-（TRPM-2）编码抗凋亡蛋白丛生，其被上调响应于蜂窝折衷作为经历凋亡正常和恶性组织中观察到。反义寡核苷酸丛生前列腺癌异种移植模型延迟进展全身给药，以人工智能和增强敏感性。这项研究的目的是确定新辅助激素治疗（NHT）在前列腺癌患者丛生表达的变化。材料和方法
分别获得谁收到要么没有NHT或治疗2-8周，3个月，或8个月的128例患者的档案前列腺癌根治术（RP）的试样。被收购的30例患者配对针吸活检标本和所有组织都受到丛生免疫组化。在冷冻组织进行Western印迹分析，于5未处理和5治疗的患者。结果
在恶性前列腺组织丛生表达显著更大谁术前NHT（P«0.001）的患者。前NHT获得穿刺活检一贯表现出更低的染色强度比对应的RP标本（P«0.001）。Western blot分析证实丛生雄激素水平停药后增加了4个星期内，17倍的开始。结论
下面的雄激素消融治疗丛生水平的上调可能是一个适应性细胞的存活响应以下凋亡信号，如雄激素撤退。这些发现支持丛生在采用新的多学科综合治疗晚期前列腺癌的策略有效的治疗靶点。前列腺50：179-188，2002。©2002威利 - 利斯公司
Laura V. July[1]; Majid Akbari[1]; Tobias Zellweger[1,2]; Edward C. Jones[3]; S. Larry Goldenberg[1,2] and Martin E. Gleave[1,2,*];. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy[J]. The Prostate, 2002,50(3): 179-188