Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer
Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer
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DOI：
10.1038/mt.2012.155
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发表时间：
2012-12-01
影响因子：
12.4
通讯作者：
Rocchi, Palma
中科院分区：
文献类型：
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作者：
Baylot, Virginie;Katsogiannou, Maria;Rocchi, Palma
热休克蛋白27（Hsp 27）在去势抵抗性前列腺癌（CRPC）中高度过表达，并且反义抑制剂（OGX-427）目前处于II期临床试验中。为了了解Hsp 27的作用机制并找到CRPC特异性的新治疗靶点，我们筛选了Hsp 27客户蛋白。在这里，我们报告，免疫控制肿瘤蛋白（TCTP）是一个新的热休克蛋白27的客户端蛋白参与热休克蛋白27的细胞保护。我们发现TCTP在正常前列腺细胞中不表达或表达较弱，在18.5%的未经治疗的PC中中度表达，在75%的CRPC中均匀且强烈表达。为了确定TCTP功能，我们开发了TCTP反义寡核苷酸（阿索）并获得全球专利。有趣的是，我们发现CRPC进展与TCTP过表达和P53丢失相关。TCTP敲低恢复P53表达和功能，表明去势敏感性与P53表达直接相关。总的来说，这些发现提供了CRPC中新的Hsp 27细胞保护机制，并且临床前概念验证表明，将ASO介导的TCTP敲低与去势和/或多西他赛治疗相结合可以作为治疗CRPC的新策略，对正常前列腺细胞没有毒性或毒性很小。
Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression. Collectively, these findings provide a new Hsp27 cytoprotection mechanism in CRPC, and preclinical proof-of-concept that combining ASO-mediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells.