Bcl-2 as a target in cancer

项目摘要 BCL-2是一种抗细胞死亡蛋白，在大约40%的人类癌症中过表达，并与 癌症的发展和进展。Bcl-2的过度表达与生存不良和 乳腺癌的进展及其与化疗药物耐药性的关系 和伽马辐射。我们发现了一种新的途径，可以将Bcl2从细胞保护性转化为 细胞破坏性蛋白。这种Bcl2功能的戏剧性变化是由孤儿核受体引起的 Nur77(在某些试剂的刺激下从细胞核迁移到线粒体)结合，它 揭示了Bc l-2的一个隐藏的“杀手BH3区域”。在识别极小泛函的过程中 Nur77的结构域，一个模拟Nur77的机制和功能活性的九个氨基酸的多肽 已被确认。这种多肽能够选择性地结合Bcl-2并转化为 BCL-2通过诱导构象变化从保护者转变为杀手蛋白。Nur77的细胞凋亡作用 Bcl2的过度表达不会抑制多肽的合成，反而会增强多肽的活性。Nur77衍生的多肽因此 代表了一类新的抗乳腺癌药物。我们已经鉴定出有选择性地诱导 提高过表达三重阴性乳腺癌细胞的死亡率。我们现在建议评估 已确定的铅“Bcl-2功能转换子”对乳腺癌干细胞的疗效。

Project Summary Bcl-2, an anti-cell death protein, is overexpressed in about 40% of all human cancers and contributes to the development and progression of cancer. Overexpression of Bcl-2 correlates with poor survival and progression of the disease and correlates with resistance of breast cancer cells to chemotherapeutic drugs and gamma irradiation. We have discovered a novel pathway to convert Bcl-2 from a cytoprotective to cytodestructive protein. This dramatic change in Bcl-2 function is brought about by orphan nuclear receptor Nur77 (which migrates from the nucleus to mitochondria upon stimulation by certain agents) binding, which exposes a hidden "killer BH3 domain" of Bcl-2. During the course of identifying the minimal functional domain of Nur77, a nine amino acid peptide that mimics the mechanistic and functional activities of Nur77 was identified. This peptide is able to induce cancer cell death by selectively binding Bcl-2 and converting Bcl-2 from a protector to a killer protein by inducing conformational changes. The apoptotic effects of Nur77 peptides are not inhibited, but rather potentiated, by Bcl-2 overexpression. Nur77-derived peptides thus represent a new class of anti-breast cancer agents. We have identified compounds that selectively induced enhanced death in Bcl-2 overexpressing triple negative breast cancer cells. We now propose to evaluate the efficacy of the identified lead ‘Bcl-2 functional converters’ on breast cancer stem cells.