FoxM1 in tumor cell

肿瘤细胞中的 FoxM1

• 批准号: 8195570
• 负责人: Pradip Raychaudhuri
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195570
• 关键词: Ablation; Antineoplastic Agents; Apoptosis; Back; Boxing; Carcinoma; Cell Cycle; Cell Cycle Progression; Cell Survival; Cell physiology; Cells; Colon; Development; Drug Delivery Systems; Drug resistance; Equilibrium; Exhibits; Family; Genes; Health; Human; Liver; Liver neoplasms; Lung; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway interactions; Peptides; Pharmaceutical Preparations; Production; Proliferating; Prostate; Reactive Oxygen Species; Regulation; Resistance; Role; Signal Pathway; Tumor Suppressor Proteins; Veterans; antitumor drug; cell injury; design; effective therapy; feeding; macromolecule; mortality; mouse model; neoplastic cell; p19ARF; premature; public health relevance; senescence; therapy resistant; transcription factor; tumor; tumor progression; tumor xenograft; tumorigenesis

Project Summary FoxM1 is a forkhead-box family transcription factor that is over-expressed in a wide variety of human cancers, including cancers of liver, colon, lung and prostate. Its over- expression in prostate cancers correlates with metastasis. In mouse models, FoxM1 is essential for development liver carcinomas, and is required for tumor progression. For example, specific inhibition of FoxM1, by a peptide derived from the tumor suppressor p19Arf, causes regression of liver tumors in mice, suggesting a critical role for FoxM1 in survival of tumor cells. Also, several studies implicated FoxM1 as a potential anticancer drug target. However, the mechanisms by which FoxM1 participates in tumorigenesis and promotes survival of tumor cells are not clear. In this proposal, we plan to investigate a newly discovered function of FoxM1 in transformation and tumor cell survival, which will be significant in the considerations of FoxM1 as an anti-tumor drug target in drug resistant tumors. We observed that FoxM1 is activated by reactive oxygen species (ROS), and that oncogenic Ras activates FoxM1 requiring ROS. Moreover, we obtained evidence for a negative feed back mechanism for regulation of ROS in which the elevated FoxM1 down regulates ROS. The negative feed back loop is critical for survival of proliferating cells in the presence of excessive ROS. FoxM1 promotes survival of tumor cells by down regulating the levels of ROS. We plan to investigate the hypotheses that FoxM1 is the pivotal regulator of ROS in proliferating cells and in tumor cells, and that the tumors cells expressing ROS-inducing oncogenes are "addicted" to FoxM1. Moreover, we will determine whether over expression of FoxM1 in tumor cells confers resistance to therapies by down regulating ROS. These studies will establish the functions of FoxM1 in tumor development and progression, as well as establish a role of FoxM1 over expression in the development of drug resistance.

项目摘要 FoxM 1是一个叉头盒家族转录因子，在广泛的细胞内过度表达， 各种人类癌症，包括肝癌、结肠癌、肺癌和前列腺癌。它结束了- 在前列腺癌中的表达与转移相关。在小鼠模型中，FoxM 1 对于肝癌的发展是必需的，并且是肿瘤进展所必需的。为 例如，通过来源于肿瘤抑制因子的肽特异性抑制FoxM 1 p19 Arf可导致小鼠肝脏肿瘤消退，提示FoxM 1在 肿瘤细胞的存活。此外，一些研究表明FoxM 1是一种潜在的抗癌药物。 药物靶点然而，FoxM 1参与肿瘤发生的机制 并促进肿瘤细胞的存活尚不清楚。在这份提案中，我们计划调查 一种新发现的FoxM 1在转化和肿瘤细胞存活中的功能， 将FoxM 1作为抗肿瘤药物靶点， 耐药肿瘤 我们观察到FoxM 1被活性氧（ROS）激活， 致癌Ras激活需要ROS的FoxM 1。此外，我们还获得了一个证据， 负反馈机制调节ROS，其中升高的FoxM 1下降 调节ROS。负反馈回路对于增殖细胞的存活至关重要， 存在过多的ROS。FoxM 1通过降低肿瘤细胞的存活率促进肿瘤细胞的存活 调节ROS的水平。我们计划调查FoxM 1是 增殖细胞和肿瘤细胞中ROS的关键调节剂，并且肿瘤细胞 表达ROS诱导癌基因的人对FoxM 1“上瘾”。而且还要 确定肿瘤细胞中FoxM 1的过表达是否赋予对 通过下调ROS进行治疗。这些研究将确定FoxM 1的功能， 在肿瘤发展和进展中的作用，以及确定FoxM 1在 在耐药性发展中的表达。