Modulation of p53 induction by targeting cap-dependent translation in cancer

通过靶向癌症中帽依赖性翻译来调节 p53 诱导

• 批准号: 8565086
• 负责人: Da-Qing Yang
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8565086
• 关键词: 5' Untranslated Regions; 8-methylguanosine; Apoptosis; Breast; Breast Cancer Cell; Cell Cycle Arrest; Cell Death; Cells; Chemicals; Code; DNA Damage; Gene Mutation; Genes; Genotoxic Stress; Goals; Growth; Growth Inhibitors; Induction of Apoptosis; Internal Ribosome Entry Site; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Messenger RNA; Mutate; Mutation; Neoplasm Metastasis; Nude Mice; Peptide Initiation Factors; Preventive; Prostate; Protein Binding; Protein p53; Proteins; Recruitment Activity; Research; Solid Neoplasm; Structure; Testing; Therapeutic; Therapeutic Agents; Translation Initiation; Translations; Tumor Suppressor Proteins; cancer cell; cancer type; cell growth; cytotoxic; genetic regulatory protein; inhibitor/antagonist; insight; malignant breast neoplasm; neoplastic cell; novel therapeutics; overexpression; public health relevance; response; treatment strategy; tumor; tumor growth; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): The p53 tumor suppressor protein protects cells against malignant transformation through induction of either cell cycle arrest or apoptosis. Since p53 is the most commonly mutated gene in cancer, the vast majority of research examining the link between p53 and cancer has been aimed at characterizing the genetic mutations that alter the p53 protein and lead to the loss of its transcriptional activity in cancer cells. However, mutations in the p53 coding region occur at a significantly lower rate in breast (20%) and prostate (18%) cancers than in other solid tumors, such as lung cancer (70%). Our results provide convincing evidence that defective p53 synthesis following DNA damage can lead to malignant transformation of breast tumor cells even though they retain the wild-type p53 coding region. Since defective p53 synthesis may be one of the key underlying mechanisms for tumorigenesis in these cancer cells, chemical compounds that can restore p53's tumor suppressive function in these cells may become highly effective preventive or therapeutic agents against cancer. Cap-dependent initiation of protein translation is used by the majority of eukaryotic mRNAs, since most of them have an N7-methylguanosine cap structure at their 5'-ends. eIF-4E is a translation initiation protein that binds to the cap structure and drives cap-dependent translation. It is known that the activity of eIF- 4E is elevated in cancer cells and its overexpression and hyperactivation cause malignant transformation and metastasis in various types of cancers, including breast and prostate cancer. Recent results have shown that inhibition of eIF-4E induces apoptosis in cancer cells. However, the underlying mechanism for induction of apoptosis by blocking cap-dependent translation is unclear. We discovered that an internal ribosome entry site (IRES) sequence is present at the 5'-untranslated region (UTR) of p53 mRNA. This is an alternate form of cap-dependent translation in which ribosomal subunits are recruited to an IRES sequence by a subset of initiation factors without the participation of eIF-4E. Multiple lines of recent evidence have revealed a new mechanism by which cap-dependent translation switches to cap-independent translation, including IRES- mediated p53 synthesis, following cyto- or genotoxic stress. Since cap-dependent translation is usually compromised by stressful conditions such as DNA damage, we hypothesize that treatment of cancer cells with inhibitors of cap-dependent translation may cause a similar transition from cap-dependent translation to IRES-mediated translation of p53, leading to apoptosis. The goal of this project is to test this hypothesis by treating cancer cells with several newly discovered cap-dependent translation inhibitors and to examine whether these inhibitors can restore p53's tumor suppressive function in non-p53 responsive cancer cells. Findings from this project will provide new insights into the functional link between suppression of cap- dependent translation and p53 induction and may lead to new therapeutic agents against cancer.

描述(由申请人提供)：P53肿瘤抑制蛋白通过诱导细胞周期停滞或凋亡来保护细胞免受恶性转化。由于P53是癌症中最常见的突变基因，因此研究P53与癌症之间的联系的绝大多数研究都是为了确定改变P53蛋白并导致其在癌细胞中失去转录活性的基因突变的特征。然而，乳腺癌(20%)和前列腺癌(18%)中p53编码区的突变率明显低于其他实体肿瘤，如肺癌(70%)。我们的结果提供了令人信服的证据，即DNA损伤后P53合成缺陷会导致乳腺肿瘤细胞恶性转化，即使它们保留了野生型P53编码区。由于P53合成缺陷可能是这些癌细胞发生肿瘤的关键机制之一，因此能够恢复这些细胞中P53‘S肿瘤抑制功能的化合物可能成为高效的癌症预防或治疗药物。大多数真核mRNAs的5‘端都有一个N7-甲基鸟苷的帽结构，因此大多数真核mRNAs都使用帽依赖的方式启动蛋白质翻译。EIF-4E是一种翻译起始蛋白，与帽结构结合并驱动帽依赖的翻译。已知eIF-4E的活性在癌细胞中升高，其 过度表达和过度激活会导致各种癌症的恶性转化和转移，包括乳腺癌和前列腺癌。最近的研究结果表明，抑制eIF-4E可以诱导癌细胞的凋亡。然而，通过阻断帽依赖的翻译来诱导细胞凋亡的潜在机制尚不清楚。我们发现在p53基因的5‘非翻译区存在一个内部核糖体进入位点(IRES)序列。这是帽依赖翻译的另一种形式，其中核糖体亚基被一组启动因子招募到IRES序列中，而不需要eIF-4E的参与。最近的一系列证据揭示了一种新的机制，即在细胞或基因毒性应激后，帽子依赖的翻译转换为帽子非依赖的翻译，包括IRES介导的P53合成。由于CAP依赖的翻译通常会受到DNA损伤等应激条件的影响，我们假设用CAP依赖翻译的抑制剂处理癌细胞可能会导致类似的从CAP依赖翻译到IRES介导的P53翻译的转变，导致细胞凋亡。该项目的目标是通过用几种新发现的帽依赖翻译抑制剂处理癌细胞来检验这一假说，并检验这些抑制剂是否能够恢复非p53反应性癌细胞的P53‘S肿瘤抑制功能。该项目的发现将为抑制帽子依赖的翻译和P53诱导之间的功能联系提供新的见解，并可能导致新的抗癌治疗药物。