Auricchio Ferdinando, Migliaccio Antimo, Castoria Gabriella
Dipartimento di Patologia Generale, II Universita'di Napoli, Via L. De Crecchio, 7, 80138 Naples, Italy.
Steroids. 2008 Oct;73(9-10):880-4. doi: 10.1016/j.steroids.2008.01.023. Epub 2008 Feb 8.
Sex-steroid hormones trigger association of their receptors with signalling effectors. Remarkably, various hormonal effects, such as DNA synthesis of different cell types are evoked by this association. In mammary and prostate cancer cells, EGF, androgen or estradiol trigger the assembly of AR/ER/Src complex. SH2-Src interacts with a phosphotyrosine residue of ER and SH3-Src interacts with a proline rich sequence of AR. This association stimulates Src-dependent signalling, DNA synthesis and cytoskeleton changes. We now report that in prostate or breast cancer cells stimulated by EGF or androgen or estradiol, small peptides (6-10 amino acids) derived from ER or AR sequences involved in the receptor interaction with Src, prevent AR/ER/Src association, Src/Erk pathway stimulation, cyclin D1 expression and DNA synthesis. The peptide action is restricted to cells expressing the steroid receptors and to signals mediated by these receptors. Remarkably, the peptides do not modify the steroid receptor-dependent transcriptional activity. Growth of prostate or mammary cancer cell xenografts is strongly inhibited by these novel receptor antagonists.
性甾体激素促使其受体与信号效应器结合。值得注意的是，这种结合会引发各种激素效应，例如不同细胞类型的DNA合成。在乳腺癌和前列腺癌细胞中，表皮生长因子（EGF）、雄激素或雌二醇会触发AR/ER/Src复合物的组装。SH2结构域的Src与雌激素受体（ER）的磷酸酪氨酸残基相互作用，而SH3结构域的Src与雄激素受体（AR）富含脯氨酸的序列相互作用。这种结合会刺激Src依赖性信号传导、DNA合成和细胞骨架变化。我们现在报告，在受EGF、雄激素或雌二醇刺激的前列腺癌或乳腺癌细胞中，源自参与受体与Src相互作用的ER或AR序列的小肽（6 - 10个氨基酸）可阻止AR/ER/Src结合、Src/Erk途径激活、细胞周期蛋白D1表达和DNA合成。肽的作用仅限于表达甾体受体的细胞以及由这些受体介导的信号。值得注意的是，这些肽不会改变甾体受体依赖性转录活性。这些新型受体拮抗剂可强烈抑制前列腺癌或乳腺癌细胞异种移植物的生长。
