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.
Veteran Health Relevance: Cancers of liver, colon, prostate and lung are common causes of mortality among veterans. FoxM1, a forkhead box transcription factor, is over-expressed in all of those cancers. Moreover, over- expression of FoxM1 in prostate cancers correlates with metastasis of the cancer. Our recent studies indicated that FoxM1 is essential for development of liver cancers in mice. The proposed studies will elucidate the cellular functions of FoxM1 that are critical for tumor cell survival and development of drug resistance. The studies will have significant impact in designing effective therapy against cancer.
|Kopanja, Dragana; Huang, Shuo; Al Raheed, Mohamed Rizwan Haroon et al. (2018) p19Arf inhibits aggressive progression of H-ras-driven hepatocellular carcinoma. Carcinogenesis 39:318-326|
|Huang, Shuo; Fantini, Damiano; Merrill, Bradley J et al. (2017) DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer. Cancer Res 77:6562-6575|
|Mukhopadhyay, Nishit K; Chand, Vaibhav; Pandey, Akshay et al. (2017) Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein. Sci Rep 7:46017|
|Fantini, Damiano; Huang, Shuo; Asara, John M et al. (2017) Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2. Mol Biol Cell 28:192-200|
|Kopanja, Dragana; Raychaudhuri, Pradip (2016) TGF? signaling: a friend or a foe to hepatic fibrosis and tumorigenesis. Ann Transl Med 4:122|
|Kopanja, Dragana; Pandey, Akshay; Kiefer, Megan et al. (2015) Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol 63:429-36|
|Wang, Zebin; Zheng, Yu; Park, Hyun Jung et al. (2013) Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma. Mol Cancer Ther 12:759-67|
|Carr, Janai R; Kiefer, Megan M; Park, Hyun Jung et al. (2012) FoxM1 regulates mammary luminal cell fate. Cell Rep 1:715-29|
|Park, Hyun Jung; Gusarova, Galina; Wang, Zebin et al. (2011) Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol Med 3:21-34|
|Wang, Zebin; Park, Hyun Jung; Carr, Janai R et al. (2011) FoxM1 in tumorigenicity of the neuroblastoma cells and renewal of the neural progenitors. Cancer Res 71:4292-302|
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