TRAIL-induced Cell Death in Breast Cancer Cells

TRAIL 诱导乳腺癌细胞死亡

• 批准号: 7969780
• 负责人: Stanley Lipkowitz
• 金额: $ 42.85万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969780
• 关键词: Agonist; Antibodies; Apoptosis; Biochemical Genetics; Breast; Breast Cancer Cell; Cancer cell line; Cell Death; Cell Death Induction; Cells; Cessation of life; Death Receptor 5; Epigenetic Process; Fenretinide; Genetic; Induction of Apoptosis; Ligands; Malignant neoplasm of ovary; Mediating; Mesenchymal; Molecular; Patients; Protein Binding; Resistance; Retinoids; TNFRSF10A gene; TNFRSF10B gene; Trastuzumab; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; base; cancer cell; chemotherapeutic agent; clinically relevant; death receptor-4; human TNFRSF10A protein; killings; malignant breast neoplasm; member; pre-clinical; receptor; triple-negative invasive breast carcinoma

Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. We are investigating the induction of apoptosis by activation of death receptors for the ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in breast and ovarian cancer cells. Previously, we have shown that many breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-ErbB-2 antibodies). Our current work utilizes biochemical and genetic approaches to identify mechanisms that regulate the induction of death by TRAIL ligand in breast and ovarian cancer cells. Recently, we have shown that TRAIL selectively kills triple-negative breast cancer cells that have mesenchymal features. Ongoing work is exploring this observation further using clinically relevant TRAIL agonists alone and incombination with other targeted agents. We are also investigating the molecular basis for this selectivity.

癌细胞通过多种遗传和表观遗传机制避免凋亡。我们正在研究通过激活乳腺癌和卵巢癌细胞中配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）的死亡受体来诱导细胞凋亡。 此前，我们已经证明许多乳腺癌和卵巢癌细胞系对 TRAIL（死亡受体 DR4 和 DR5 的配体）诱导的细胞凋亡具有抵抗力。我们已经证明，通过将细胞与化疗剂、半合成类维生素A（例如4HPR）或分子靶向剂（例如抗ErbB-2抗体）共孵育，可以克服对TRAIL诱导的细胞凋亡的抵抗。我们目前的工作利用生化和遗传学方法来确定在乳腺癌和卵巢癌细胞中调节 TRAIL 配体诱导死亡的机制。最近，我们发现 TRAIL 选择性杀死具有间质特征的三阴性乳腺癌细胞。正在进行的工作正在进一步探索这一观察结果，单独使用临床相关的 TRAIL 激动剂或与其他靶向药物联合使用。我们还在研究这种选择性的分子基础。