MDM2 regulates XIAP gene expression in cancer treatment

描述（由申请人提供）：癌症治疗失败的一个主要原因是癌细胞对放疗和化疗的耐药性，这被认为是由于癌基因或抗凋亡因子的异常表达和失调，或很可能是这些因素的结合。我们发现，在癌症治疗过程中，MDM2癌基因的过度表达上调了细胞凋亡抑制蛋白XIAP，并且它与放化疗后癌细胞的存活和对细胞凋亡的抵抗有关。我们也已经知道，细胞核中的MDM2及其磷酸化形式，受PI3K/Akt生存信号的调控，可以结合并抑制p53活性。此外，MDM2在肿瘤发生中发挥p53独立的作用，其机制尚不完全清楚。本项目的目的是确定在癌症治疗过程中，MDM2在调节XIAP翻译过程中的p53独立作用，并评估靶向MDM2-XIAP信号通路用于治疗耐药癌症患者的潜力。初步研究表明，在辐射的作用下，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应激刺激（包括放疗和化疗）调控MDM2并随后诱导XIAP翻译的分子机制，并建立MDM2在细胞水平上调控XIAP翻译与患者群体对抗癌治疗反应之间的联系。本项目的具体目的是：1)研究MDM2通过内部核糖体进入位点（IRES）依赖途径在调节XIAP翻译中的p53非依赖性作用，并表征MDM2蛋白与XIAP IRES之间的相互作用；2)确定mdm2介导的XIAP翻译与抗癌治疗引发的细胞应激信号应答之间的联系；3)通过MDM2蛋白与XIAP mRNA的相互作用抑制XIAP的翻译，寻求一种新的癌症治疗方法。由于肿瘤细胞过表达MDM2的各类癌症患者的生存率仍然很低，我们的研究可能有助于产生新的知识，可以扩展我们目前对放疗和化疗耐药的理解，并为合理设计可用于治疗这些难治性癌症患者的新药提供基本框架。更多的以知识为基础的方法来治疗耐药和进展中的癌症患者在抗癌治疗库中是非常需要的。我们的研究应该有助于为难治性癌症患者提供一些急需的治疗方法。

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.