HUMAN BREAST CANCER CELL GROWTH INHIBITION BY VITAMIN E

维生素 E 抑制人类乳腺癌细胞生长

• 批准号: 2895025
• 负责人: KIMBERLY KLINE
• 金额: $ 19.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895025
• 关键词: MCF7 cell; apoptosis; breast neoplasms; cell growth regulation; cell line; gene induction /repression; growth factor receptors; human tissue; neoplastic growth; protein kinase; protooncogene; receptor expression; tissue /cell culture; tocopherols; transcription factor; transforming growth factors; vitamin analog

This proposal is designed to investigate the hypothesis that vitamin E succinate (VES) causes tumor cell death by induction of apoptosis via the dual action of increasing negative growth factor (TGF-( ) signaling pathway and enhancing stress response signaling pathway (SAPKs/JNKs) which coverage on AP-1 transcription factors, leading to either repression of genes necessary for survival or stimulation of genes associated with suicide function. Initial studies indicated that VES induced greater than 70 percent of cultured human breast cancer cells (MCF-7 and MDA-MB-435) to undergo apoptosis after 4 days of treatment. Support for the dual signaling pathways comes from indirect evidence showing increased ERK and JNK activities in VES-treated cells. Exposure to VES was also found to induce prolonged elevation of c-jun mRNA and protein. This was accompanied by increased nuclear protein binding to AP-1 and to CRE consensus sequences as well as increased transactivation activity as monitored by AP-1 dependent reporter gene expression. The specific aims of the proposal are (1) to determine the contribution of AP-1 constituents to VES-induced apoptosis in human breast cancer cells, and (2) to characterize the contributions of JNK and ERK to VES-induced apoptosis. The models for the research will include both the estrogen-responsive MCG-7 cells, as well as the estrogen- unresponsive MDA-MB-435 cells. Cells that are stably or transiently transfected with a variety of gene constructs will also be employed in various aspects of the proposed studies.

该建议旨在研究维生素E的假设 琥珀酸酯（VES）通过通过诱导凋亡而导致肿瘤细胞死亡 增加负生长因子的双重作用（TGF-（）信号传导 途径并增强应力响应信号通路（SAPK/JNK） AP-1转录因子的覆盖范围，导致这两种 抑制生存或刺激基因所必需的基因 与自杀功能相关。 初步研究表明VES 诱导超过70％的培养的人类乳腺癌细胞 （MCF-7和MDA-MB-435）治疗4天后会凋亡。 双重信号通路的支持来自间接证据 显示了经VES处理的细胞中ERK和JNK活性的增加。 还发现暴露于VES会引起长时间的C-Jun升高 mRNA和蛋白质。 伴随着核蛋白的增加 与AP-1和CRE共识序列结合并增加 由AP-1依赖性记者基因监测的反式激活活性 表达。 该提案的具体目的是（1）确定 AP-1成分对人类VES诱导的凋亡的贡献 乳腺癌细胞，（2）表征JNK和 ERK到VES诱导的凋亡。 研究模型将包括 雌激素反应性MCG-7细胞以及雌激素 - 无反应的MDA-MB-435细胞。 稳定或瞬时的细胞 用多种基因构建体转染的 拟议研究的各个方面。