FoxM1 in tumor cell

描述（由申请人提供）： FoxM1是一种叉头盒家族转录因子，在多种人类癌症中过度表达，包括肝癌、结肠癌、肺癌和前列腺癌。它在前列腺癌中的过表达与转移有关.在小鼠模型中，FoxM1对于肝癌的发展至关重要，并且是肿瘤进展所必需的。例如，由肿瘤抑制因子p19Arf衍生的肽对FoxM1的特异性抑制导致小鼠肝脏肿瘤的消退，表明FoxM1在肿瘤细胞存活中的关键作用。此外，一些研究表明FoxM1是潜在的抗癌药物靶点。然而，FoxM1参与肿瘤发生和促进肿瘤细胞存活的机制尚不清楚。在这个提议中，我们计划研究FoxM1在转化和肿瘤细胞存活中的新发现的功能，这将在考虑FoxM1作为耐药肿瘤中的抗肿瘤药物靶点方面具有重要意义。我们观察到FoxM1被活性氧（ROS）激活，致癌Ras激活FoxM1需要ROS。此外，我们获得的证据表明，负反馈机制的调节活性氧，其中升高的FoxM1下调活性氧。负反馈回路对于在过量ROS存在下增殖细胞的存活至关重要。FoxM1通过下调ROS水平促进肿瘤细胞的存活。我们计划调查的假设，FoxM1是在增殖细胞和肿瘤细胞中的ROS的关键调节器，并表达ROS诱导癌基因的肿瘤细胞是“上瘾”FoxM1。此外，我们将确定肿瘤细胞中FoxM1的过度表达是否通过下调ROS而赋予对治疗的抗性。这些研究将确定FoxM1在肿瘤发展和进展中的功能，以及FoxM1过表达在耐药性发展中的作用。

DESCRIPTION (provided by applicant): 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.