A major cause for the failure of cancer treatment is the resistance of cancer cells to radiotherapy and chemotherapy, which is believed to be due to abnormal expression and deregulation of oncogenes or anti-apoptotic factors, or most likely a combination of these. We have found that the inhibitor-of-apoptosis protein XIAP is upregulated by the overexpression of the MDM2 oncogene during cancer treatment, and it has been linked to cancer cell survival and resistance to apoptosis following radiation and chemotherapy. It is also already known that MDM2 in the nucleus and its phosphorylated form, which is regulated by PI3K/Akt survival signaling, can bind to and inhibit p53 activity. In addition, MDM2 exerts a p53-independent role in oncogenesis by mechanisms that are not completely understood. The goals of this project are to determine the p53- independent role of MDM2 in regulating XIAP translation in the development of drug resistance during cancer therapy and to evaluate the potential for targeting the MDM2-XIAP signaling pathway for use in the treatment of drug-resistant cancer patients. Preliminary studies have demonstrated that, in response to radiation, MDM2 is dephosphorylated and localized in the cytoplasm, where it can directly elevate XIAP protein levels. The proposed study seeks to further clarify the molecular mechanisms by which stress stimulation, including radiation and chemotherapy, modulates MDM2 and subsequently induces XIAP translation as well as to establish the linkage between MDM2's regulation of XIAP translation at the cellular level and the patient population's response to anticancer treatment.
The specific aims of this project are: 1) To investigate the p53-independent role of MDM2 in regulating XIAP translation through an internal ribosome entry site (IRES)-dependent pathway and to characterize the interaction between the MDM2 protein and XIAP IRES;2) To determine the link between MDM2-mediated XIAP translation and the response to cellular stress signaling triggered by anticancer treatment;3) To target the MDM2 protein/XIAP mRNA interaction in order to inhibit XIAP translation, towards developing a novel approach to cancer treatment. Because the survival of various types of cancer patients whose neoplastic cells overexpress MDM2 remains very poor, our studies may help generate knowledge that can extend our current understanding of resistance to radiotherapy and chemotherapy and provide the basic framework for the rational design of new agents that can be used to treat these refractory cancer patients. More knowledge-based ways to treat patients with resistant and advancing cancers are greatly needed in the anticancer therapy arsenal. Our research should help pave a new path towards some of these much needed treatments for patients with refractory cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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Emory University
Schools of Medicine
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Zhang, Hailong; Gu, Lubing; Liu, Tao et al. (2014) Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia. PLoS One 9:e100960
Li, Jiansha; Gu, Lubing; Zhang, Hailong et al. (2013) Berberine represses DAXX gene transcription and induces cancer cell apoptosis. Lab Invest 93:354-64
Huang, Mei; Zhang, Hailong; Liu, Tao et al. (2013) Triptolide inhibits MDM2 and induces apoptosis in acute lymphoblastic leukemia cells through a p53-independent pathway. Mol Cancer Ther 12:184-94
Zhang, Hailong; He, Jing; Li, Jiansha et al. (2013) Methylation of RASSF1A gene promoter is regulated by p53 and DAXX. FASEB J 27:232-42
Gu, L; Zhang, H; He, J et al. (2012) MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells. Oncogene 31:1342-53
Zhou, Sheng; Gu, Lubing; He, Jing et al. (2011) MDM2 regulates vascular endothelial growth factor mRNA stabilization in hypoxia. Mol Cell Biol 31:4928-37
He, Jing; Gu, Lubing; Zhang, Hailong et al. (2011) Crosstalk between MYCN and MDM2-p53 signal pathways regulates tumor cell growth and apoptosis in neuroblastoma. Cell Cycle 10:2994-3002
Yang, Lin; Gu, Lubing; Li, Zhuoya et al. (2010) Translation of TRAF1 is regulated by IRES-dependent mechanism and stimulated by vincristine. Nucleic Acids Res 38:4503-13
Zhang, Xiaoling; Gu, Lubing; Li, Jiansha et al. (2010) Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res 70:9895-904
Gu, Lubing; Zhu, Ningxi; Zhang, Hongying et al. (2009) Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell 15:363-75

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