Gleave Martin, Miyake Hideaki
Division of Urology, University of British Columbia, D-9, 2733 Heather Street, Vancouver, British Columbia , V5Z 3J5, Canada.
World J Urol. 2005 Feb;23(1):38-46. doi: 10.1007/s00345-004-0474-0. Epub 2005 Jan 26.
The discovery and targeting of genes mediating androgen-independence may lead to the development of novel therapies that delay progression of hormone refractory prostate cancer (HRPC). Clusterin is a stress-associated cell survival gene that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the use of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer models. Immunostaining of tissue microarrays constructed from untreated and post-hormone treated radical prostatectomy specimens confirm that clusterin is highly expressed in virtually all HRPC cells, 80% of prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Overexpression of clusterin in LNCaP cells confers resistance to both androgen ablation and chemotherapy. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels, accelerated apoptotic tumor regression, and significantly delayed the recurrence of androgen-independent tumors. A human clusterin ASO targeting the translation initiation site and incorporating MOE-gapmer backbone (OGX-011) synergistically enhanced the cytotoxic effects of paclitaxel in human xenografts of prostate, renal cell, bladder, and lung cancer. Clusterin, is an anti-apoptosis protein upregulated in an adaptive cell survival manner by androgen ablation and chemotherapy that confers resistance to various cell death triggers. Suppression of clusterin levels using ASOs enhances cell death following treatment with androgen ablation, radiation, and chemotherapy.
介导雄激素非依赖性的基因的发现及靶向作用可能会带来新型疗法的开发，从而延缓激素难治性前列腺癌（HRPC）的进展。簇集素是一种与应激相关的细胞存活基因，在雄激素去除后会增加。在此，我们综述簇集素在细胞凋亡中的功能作用，以及使用针对簇集素的反义寡核苷酸（ASO）来增强前列腺癌模型中的细胞凋亡。对由未经治疗和激素治疗后的根治性前列腺切除术标本构建的组织微阵列进行免疫染色证实，簇集素在几乎所有HRPC细胞、新辅助激素治疗后80%的前列腺癌细胞中高表达，但在未经治疗的标本中低表达或无表达（<20%）。簇集素在LNCaP细胞中的过表达赋予了对雄激素去除和化疗的抗性。簇集素ASO以剂量依赖性和序列特异性方式降低簇集素水平。对携带Shionogi肿瘤的小鼠去势后，用鼠源簇集素ASO进行辅助治疗可降低簇集素水平，加速肿瘤凋亡消退，并显著延迟雄激素非依赖性肿瘤的复发。一种靶向翻译起始位点并包含吗啉代缺口聚物骨架的人簇集素ASO（OGX-011）可协同增强紫杉醇对人前列腺癌、肾细胞癌、膀胱癌和肺癌异种移植瘤的细胞毒性作用。簇集素是一种抗凋亡蛋白，通过雄激素去除和化疗以适应性细胞存活方式上调，赋予对各种细胞死亡触发因素的抗性。使用ASO抑制簇集素水平可增强雄激素去除、放疗和化疗治疗后的细胞死亡。
