Bcl-2 as a target in cancer

Bcl-2 作为癌症靶点

• 批准号: 10321294
• 负责人: Siva Kumar Kolluri
• 金额: $ 20.41万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321294
• 关键词: Aftercare; Amino Acids; Antisense Oligonucleotides; Apoptosis; Apoptotic; BCL-2 Protein; BCL2 gene; BCL2L1 gene; BH3 Domain; BH3 peptide; Binding; Breast; Breast Cancer Cell; Cell Death; Cell Line; Cell Nucleus; Cells; Cessation of life; Chemoresistance; Chemotherapy-Oncologic Procedure; Development; Disease Progression; Family member; Heterodimerization; Human; Hydrophobicity; Investigation; Lead; MCL1 gene; Malignant Neoplasms; Mediating; Mitochondria; Molecular; Molecular Conformation; Mus; NR4A1 gene; Neoplasm Metastasis; Nuclear Orphan Receptor; Nuclear Receptors; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Primary Neoplasm; Prognosis; Property; Proteins; Proteolysis; Research; Resistance; Role; Solid; Testing; Therapeutic; Therapeutic Agents; Xenograft procedure; anti-cancer; cancer cell; cancer stem cell; cancer subtypes; clinical translation; cytochrome c; efficacy evaluation; functional mimics; gamma irradiation; in vivo; inhibitor; leukemia/lymphoma; malignant breast neoplasm; member; novel; novel lead compound; overexpression; peptidomimetics; pro-apoptotic protein; small molecule; small molecule libraries; stem cell growth; targeted treatment; therapy resistant; three dimensional cell culture; triple-negative invasive breast carcinoma; tumor growth; tumor progression

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.

项目概要 Bcl-2 是一种抗细胞死亡蛋白，在约 40% 的人类癌症中过度表达，并有助于 癌症的发生和进展。 Bcl-2 过度表达与生存率低下相关 疾病的进展与乳腺癌细胞对化疗药物的耐药性相关 和伽马射线照射。我们发现了一种将 Bcl-2 从细胞保护作用转变为细胞保护作用的新途径 细胞破坏蛋白。 Bcl-2功能的这种巨大变化是由孤儿核受体带来的 Nur77（在某些物质的刺激下从细胞核迁移到线粒体）结合，这 暴露了 Bcl-2 的隐藏“杀手 BH3 结构域”。在确定最小功能的过程中 Nur77 的结构域，一种九个氨基酸的肽，模拟 Nur77 的机制和功能活性 被识别出来。该肽能够通过选择性结合 Bcl-2 并将其转化来诱导癌细胞死亡。 Bcl-2 通过诱导构象变化从保护蛋白转变为杀伤蛋白。 Nur77 的细胞凋亡作用 Bcl-2 过度表达不会抑制肽，而是会增强肽。 Nur77衍生肽因此 代表了一类新的抗乳腺癌药物。我们已经鉴定出选择性诱导的化合物 Bcl-2 过表达三阴性乳腺癌细胞死亡增加。我们现在建议评估 已确定的先导“Bcl-2 功能转换器”对乳腺癌干细胞的功效。