MDM2 regulates XIAP gene expression in cancer treatment

描述(申请人提供)：癌症治疗失败的一个主要原因是癌细胞对放射和化疗的抗药性，这被认为是由于癌基因或抗凋亡因子的异常表达和解除调控，或者很可能是这些因素的组合。我们发现，在肿瘤治疗过程中，MDM2癌基因的过度表达上调了凋亡抑制蛋白XIAP，它与放化疗后癌细胞的存活和抗凋亡有关。也已经知道，细胞核中的MDM2及其磷酸化形式受PI3K/Akt生存信号的调节，可以与P53结合并抑制P53活性。此外，MDM2通过尚未完全了解的机制在肿瘤发生中发挥不依赖于P53的作用。本项目的目标是确定MDM2在癌症治疗过程中调节XIAP翻译过程中的p53非依赖性作用，并评估靶向MDM2-XIAP信号通路用于治疗耐药癌症患者的可能性。初步研究表明，作为对辐射的响应，MDM2被去磷酸化并定位于细胞质中，在那里它可以直接提高XIAP蛋白水平。本研究旨在进一步阐明包括放疗和化疗在内的应激刺激调节MDM2并随后诱导XIAP翻译的分子机制，以及建立MDM2的S在细胞水平上调节XIAP翻译与患者群体对抗癌治疗的反应之间的联系。本项目的具体目标是：1)研究MDM2通过依赖内部核糖体进入位点(IRES)的途径调节XIAP翻译的非p53依赖的作用，并表征MDM2蛋白与XIAP IRES之间的相互作用；2)确定MDM2介导的XIAP翻译与抗癌治疗触发的细胞应激信号反应之间的联系；3)靶向MDM2蛋白/XIAP mRNA的相互作用以抑制XIAP翻译，从而开发一种新的癌症治疗方法。由于肿瘤细胞过度表达MDM2的各种癌症患者的存活率仍然非常低，我们的研究可能有助于产生知识，这些知识可以扩展我们目前对放疗和化疗耐药性的理解，并为合理设计可用于治疗这些难治性癌症患者的新药物提供基本框架。在抗癌治疗的武器库中，迫切需要更多基于知识的方法来治疗耐药和进展期癌症患者。我们的研究应该有助于为难治性癌症患者铺平一条新的道路，实现这些亟需的治疗。

DESCRIPTION (provided by applicant): 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.