Lyn is a target gene for prostate cancer:: Sequence-based inhibition induces regression of human tumor xenografts
Lyn is a target gene for prostate cancer:: Sequence-based inhibition induces regression of human tumor xenografts
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DOI：
10.1158/0008-5472.can-03-2420
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Ben-Sasson, SA
中科院分区：
文献类型：
--
作者：
Goldenberg-Furmanov, M;Stein, I;Ben-Sasson, SA
src相关蛋白激酶Lyn在b细胞活化中起重要作用。然而，一些证据表明，它也参与控制细胞增殖和抑制细胞凋亡。我们发现Lyn在正常前列腺上皮、95%的原发性人前列腺癌（PC）标本以及我们检测的所有PC细胞系中表达。此外，Lyn基因敲除小鼠显示前列腺形态发生异常，这表明Lyn在前列腺上皮发育中起重要作用，并暗示Lyn是特异性治疗PC的候选靶点。利用药物设计策略构建基于序列的肽抑制剂，合成了针对Lyn内部独特相互作用位点的Lyn特异性抑制剂KRX-123。KRX-123在DU145、PC3和TSU-Pr1三种激素难耐的PC细胞株中均有抑制细胞增殖的作用，IC50值为2 ~ 4 μ m。在体内，KRX-123注射剂量为10 mg/kg，每周1次，连续5周后，裸鼠DU145外植体肿瘤体积显著减少。治疗后肿瘤的组织学分析显示广泛的细胞凋亡。因此，我们认为Lyn抑制可能是治疗激素难治性PC的主要靶点。
The Src-related protein kinase Lyn plays an important role in B-cell activation. However, several lines of evidence suggest that it is also involved in the control of cellular proliferation and the inhibition of apoptosis. We have discovered that Lyn is expressed in normal prostate epithelia, in 95% of primary human prostate cancer (PC) specimens examined, and in all of the PC cell lines that we assayed. Moreover, Lyn knockout mice display abnormal prostate gland morphogenesis, which suggests that Lyn plays an important role in prostate epithelium development and implies that Lyn is a candidate target for specific therapy for PC. Using a drug-design strategy to construct sequence-based peptide inhibitors, a Lyn-specific inhibitor, KRX-123, targeting a unique interaction site within Lyn, was synthesized. KRX-123 was found to inhibit cellular proliferation in three hormone-refractory PC cell lines, DU145, PC3, and TSU-Pr1 with IC50 values of 2-4 mum. In vivo, tumor volume of DU145 explants in nude mice was significantly reduced after once-a-week injections of KRX-123, at a dose of 10 mg/kg, for a period of 5 weeks. Histological analyses of the treated tumors indicated extensive apoptosis. Thus, we suggest that Lyn inhibition may serve as a prime target for the treatment of hormone-refractory PC.