Migliaccio A, Varricchio L, De Falco A, Castoria G, Arra C, Yamaguchi H, Ciociola A, Lombardi M, Di Stasio R, Barbieri A, Baldi A, Barone M V, Appella E, Auricchio F
Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, II Università di Napoli, Via L De Crecchio, Napoli, Italia.
Oncogene. 2007 Oct 11;26(46):6619-29. doi: 10.1038/sj.onc.1210487. Epub 2007 May 7.
In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor (EGF) trigger association of the androgen receptor (AR)-estradiol receptor (ER) (alpha or beta) complex with Src. This interaction activates Src and affects the G1 to S cell cycle progression. In this report, we identify the sequence responsible for the AR/Src interaction and describe a 10 amino-acid peptide that inhibits this interaction. Treatment of the human prostate or mammary cancer cells (LNCaP or MCF-7, respectively) with nanomolar concentrations of this peptide inhibits the androgen- or estradiol-induced association between the AR or the ER and Src the Src/Erk pathway activation, cyclin D1 expression and DNA synthesis, without interfering in the receptor-dependent transcriptional activity. Similarly, the peptide prevents the S phase entry of LNCaP and MCF-7 cells treated with EGF as well as mouse embryo fibroblasts stimulated with androgen or EGF. Interestingly, the peptide does not inhibit the S phase entry and cytoskeletal changes induced by EGF or serum treatment of AR-negative prostate cancer cell lines. The peptide is the first example of a specific inhibitor of steroid receptor-dependent signal transducing activity. The importance of these results is highlighted by the finding that the peptide strongly inhibits the growth of LNCaP xenografts established in nude mice.
在人乳腺癌和前列腺癌细胞中，类固醇激素或表皮生长因子（EGF）可促使雄激素受体（AR）-雌二醇受体（ER，α或β）复合物与Src发生结合。这种相互作用激活了Src，并影响细胞从G1期到S期的进程。在本报告中，我们确定了负责AR/Src相互作用的序列，并描述了一种能抑制这种相互作用的10个氨基酸的肽段。用纳摩尔浓度的该肽段处理人前列腺癌细胞或乳腺癌细胞（分别为LNCaP或MCF-7），可抑制雄激素或雌二醇诱导的AR或ER与Src之间的结合、Src/Erk信号通路的激活、细胞周期蛋白D1的表达及DNA合成，且不会干扰受体依赖性转录活性。同样，该肽段可阻止经EGF处理的LNCaP和MCF-7细胞以及经雄激素或EGF刺激的小鼠胚胎成纤维细胞进入S期。有趣的是，该肽段不会抑制AR阴性前列腺癌细胞系经EGF或血清处理诱导的S期进入及细胞骨架变化。该肽段是类固醇受体依赖性信号转导活性特异性抑制剂的首个实例。该肽段能强烈抑制裸鼠体内建立的LNCaP异种移植物的生长，这一发现凸显了这些结果的重要性。
