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

描述（由申请人提供）：p53肿瘤抑制蛋白通过诱导细胞周期阻滞或细胞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，绝大多数研究p53与癌症之间的联系的研究都旨在描述改变p53蛋白并导致其在癌细胞中转录活性丧失的基因突变。然而，p53编码区突变在乳腺癌（20%）和前列腺癌（18%）中的发生率明显低于其他实体肿瘤（如肺癌（70%））。我们的研究结果提供了令人信服的证据，证明DNA损伤后的p53合成缺陷可以导致乳腺肿瘤细胞的恶性转化，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，在这些细胞中恢复p53抑瘤功能的化合物可能成为非常有效的癌症预防或治疗药物。大多数真核mrna都使用帽依赖性蛋白翻译起始，因为它们大多数在其5'端具有n7 -甲基鸟苷帽结构。eIF-4E是一种结合帽结构并驱动帽依赖性翻译的翻译起始蛋白。众所周知，eIF- 4E的活性在癌细胞及其肿瘤细胞中升高

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.